Jim Kling

San Antonio – Taxane exposure during pregnancy appears to be safe for mothers and offspring, according to a new retrospective cohort analysis. The findings shed light on a relatively unstudied topic. “Our cohort with 103 patients represents the most extensive study to date, and our main goal was to have homogeneous reporting of adverse events,” Ana Ferrigno Guajardo, MD, said in an interview. She presented the results at the San Antonio Breast Cancer Symposium.

“Breast cancer during pregnancy is a very challenging clinical situation as the expected antineoplastic effects of treatment must be carefully balanced against potential detrimental consequences on the developing fetus,” said Dr. Guajardo. She is a resident physician at Yale University School of Medicine.

Anthracycline-based chemotherapy agents are generally used during pregnancy because there is more safety data available for them, but some studies have shown that taxanes may have better efficacy in some clinical situations. “Cohort studies that have been done in the past [show] that taxane use is mostly deferred to the postpartum period, and we are not really sure of the impact that can have on survival in patients postponing treatment,” said Dr. Guajardo.

There are potential safety concerns with taxanes because neonates lack the cytochrome enzymes to metabolize the drugs, which creates a theoretical risk of adverse effects due to prolonged activity. On the other hand, pregnant women metabolize taxanes faster, and there are placental barriers that can inhibit high molecular weight molecules like taxanes from reaching the fetus, according to Dr. Guajardo.

In addition to pregnancy outcomes, the researchers followed 28 infants, and found that 87% were found to be completely healthy, “so we were relatively reassured. But of course we think that there’s a need for prospective studies that validate our findings regarding the safety taxanes,” said Dr. Guajardo.

Although there is no direct comparison group, the findings correlate well with studies of the general population and other chemotherapy agents. “We have large cohorts with mostly anthracycline-based chemotherapy agents during pregnancy that we can compare our results to, and overall, we were reassured that the prevalence of complications that we found in our cohort was very similar or even lower to those reported in the literature with patients treated with anthracycline-based therapy,” said Dr. Guajardo.

Compared with the general population, the team found higher rates of preterm births, neonatal ICU admissions, and premature membrane rupture, and infants that are small for gestational age. However, with the exception of the latter, all of these risks have been seen in pregnant women treated with other types of chemotherapy. “Perhaps it would be interesting to see if the incidence of small for gestational age neonates might be a bit higher in this population when compared to anthracycline-based therapy agents, but that does require a study that has a comparator group,” said Dr. Guajardo.

The researchers recruited 103 women with an average age of 34 years from 10 centers in 6 countries: United States, France, Spain, Mexico, Italy, and Costa Rica. The great majority were also treated with anthracyclines during gestation, and nearly all (97%) were treated with paclitaxel. The live birth rate was 98%, and 43.4% were preterm, 24% were small for gestational age, 16% were admitted to the neonate ICU, and 12.5% had hyperbilirubinemia.

Obstetric complications included intrauterine growth restriction (9%), preterm premature rupture of membranes (5%), gestational diabetes mellitus (5%), hypertensive disorders (4%), and pregnancy loss (2%).

After the presentation, Virginia Borges, MD, professor of medical oncology at University of Colorado Anschutz Medical Center, served as a discussant.

“Highlights of this study [include] that it is an international cohort from over six countries with over 100 cases of women included specifically focusing on the use of paclitaxel. They demonstrated safe outcomes for the pregnancies and the mothers,” Dr. Borges said during her presentation.

She went on to highlight several key points that physicians should consider when treating pregnancy-related breast cancer. “We want to achieve prepartum treatment wherever feasible to tackle that cancer before delivery of the child to prevent a pregnancy-related breast cancer from potentially turning into a postpartum breast cancer,” she said.

“If the tumor is ER+/HER2-, we now see we can safely give anthracyclines and taxanes from 12 to about 35 weeks of gestation. We don’t want to get too close to the delivery with chemotherapy. If a patient is HER2+, I prefer to give the anthracycline portion while the person is pregnant and then after delivery incorporate the taxane with the HER2 targeted therapies as there’s some older data showing concurrent therapy looks a bit better than sequential. In triple negative breast cancer, again I prefer to give the anthracycline and delay the taxane and carboplatin to overlap with immunotherapy so we are getting the necessary synergy there as well,” Dr. Borges added.

Dr. Guajardo has no relevant financial disclosures. Dr. Borges has consulted for SeaGen, Gilead, and AstraZeneca, and has received research funding from AstraZeneca, Gilead, Olema, and SeaGen.

San Antonio – Taxane exposure during pregnancy appears to be safe for mothers and offspring, according to a new retrospective cohort analysis. The findings shed light on a relatively unstudied topic. “Our cohort with 103 patients represents the most extensive study to date, and our main goal was to have homogeneous reporting of adverse events,” Ana Ferrigno Guajardo, MD, said in an interview. She presented the results at the San Antonio Breast Cancer Symposium.

“Breast cancer during pregnancy is a very challenging clinical situation as the expected antineoplastic effects of treatment must be carefully balanced against potential detrimental consequences on the developing fetus,” said Dr. Guajardo. She is a resident physician at Yale University School of Medicine.

Anthracycline-based chemotherapy agents are generally used during pregnancy because there is more safety data available for them, but some studies have shown that taxanes may have better efficacy in some clinical situations. “Cohort studies that have been done in the past [show] that taxane use is mostly deferred to the postpartum period, and we are not really sure of the impact that can have on survival in patients postponing treatment,” said Dr. Guajardo.

There are potential safety concerns with taxanes because neonates lack the cytochrome enzymes to metabolize the drugs, which creates a theoretical risk of adverse effects due to prolonged activity. On the other hand, pregnant women metabolize taxanes faster, and there are placental barriers that can inhibit high molecular weight molecules like taxanes from reaching the fetus, according to Dr. Guajardo.

In addition to pregnancy outcomes, the researchers followed 28 infants, and found that 87% were found to be completely healthy, “so we were relatively reassured. But of course we think that there’s a need for prospective studies that validate our findings regarding the safety taxanes,” said Dr. Guajardo.

Although there is no direct comparison group, the findings correlate well with studies of the general population and other chemotherapy agents. “We have large cohorts with mostly anthracycline-based chemotherapy agents during pregnancy that we can compare our results to, and overall, we were reassured that the prevalence of complications that we found in our cohort was very similar or even lower to those reported in the literature with patients treated with anthracycline-based therapy,” said Dr. Guajardo.

Compared with the general population, the team found higher rates of preterm births, neonatal ICU admissions, and premature membrane rupture, and infants that are small for gestational age. However, with the exception of the latter, all of these risks have been seen in pregnant women treated with other types of chemotherapy. “Perhaps it would be interesting to see if the incidence of small for gestational age neonates might be a bit higher in this population when compared to anthracycline-based therapy agents, but that does require a study that has a comparator group,” said Dr. Guajardo.

The researchers recruited 103 women with an average age of 34 years from 10 centers in 6 countries: United States, France, Spain, Mexico, Italy, and Costa Rica. The great majority were also treated with anthracyclines during gestation, and nearly all (97%) were treated with paclitaxel. The live birth rate was 98%, and 43.4% were preterm, 24% were small for gestational age, 16% were admitted to the neonate ICU, and 12.5% had hyperbilirubinemia.

Obstetric complications included intrauterine growth restriction (9%), preterm premature rupture of membranes (5%), gestational diabetes mellitus (5%), hypertensive disorders (4%), and pregnancy loss (2%).

After the presentation, Virginia Borges, MD, professor of medical oncology at University of Colorado Anschutz Medical Center, served as a discussant.

“Highlights of this study [include] that it is an international cohort from over six countries with over 100 cases of women included specifically focusing on the use of paclitaxel. They demonstrated safe outcomes for the pregnancies and the mothers,” Dr. Borges said during her presentation.

She went on to highlight several key points that physicians should consider when treating pregnancy-related breast cancer. “We want to achieve prepartum treatment wherever feasible to tackle that cancer before delivery of the child to prevent a pregnancy-related breast cancer from potentially turning into a postpartum breast cancer,” she said.

“If the tumor is ER+/HER2-, we now see we can safely give anthracyclines and taxanes from 12 to about 35 weeks of gestation. We don’t want to get too close to the delivery with chemotherapy. If a patient is HER2+, I prefer to give the anthracycline portion while the person is pregnant and then after delivery incorporate the taxane with the HER2 targeted therapies as there’s some older data showing concurrent therapy looks a bit better than sequential. In triple negative breast cancer, again I prefer to give the anthracycline and delay the taxane and carboplatin to overlap with immunotherapy so we are getting the necessary synergy there as well,” Dr. Borges added.

Dr. Guajardo has no relevant financial disclosures. Dr. Borges has consulted for SeaGen, Gilead, and AstraZeneca, and has received research funding from AstraZeneca, Gilead, Olema, and SeaGen.

San Antonio – Taxane exposure during pregnancy appears to be safe for mothers and offspring, according to a new retrospective cohort analysis. The findings shed light on a relatively unstudied topic. “Our cohort with 103 patients represents the most extensive study to date, and our main goal was to have homogeneous reporting of adverse events,” Ana Ferrigno Guajardo, MD, said in an interview. She presented the results at the San Antonio Breast Cancer Symposium.

“Breast cancer during pregnancy is a very challenging clinical situation as the expected antineoplastic effects of treatment must be carefully balanced against potential detrimental consequences on the developing fetus,” said Dr. Guajardo. She is a resident physician at Yale University School of Medicine.

Anthracycline-based chemotherapy agents are generally used during pregnancy because there is more safety data available for them, but some studies have shown that taxanes may have better efficacy in some clinical situations. “Cohort studies that have been done in the past [show] that taxane use is mostly deferred to the postpartum period, and we are not really sure of the impact that can have on survival in patients postponing treatment,” said Dr. Guajardo.

There are potential safety concerns with taxanes because neonates lack the cytochrome enzymes to metabolize the drugs, which creates a theoretical risk of adverse effects due to prolonged activity. On the other hand, pregnant women metabolize taxanes faster, and there are placental barriers that can inhibit high molecular weight molecules like taxanes from reaching the fetus, according to Dr. Guajardo.

In addition to pregnancy outcomes, the researchers followed 28 infants, and found that 87% were found to be completely healthy, “so we were relatively reassured. But of course we think that there’s a need for prospective studies that validate our findings regarding the safety taxanes,” said Dr. Guajardo.

Although there is no direct comparison group, the findings correlate well with studies of the general population and other chemotherapy agents. “We have large cohorts with mostly anthracycline-based chemotherapy agents during pregnancy that we can compare our results to, and overall, we were reassured that the prevalence of complications that we found in our cohort was very similar or even lower to those reported in the literature with patients treated with anthracycline-based therapy,” said Dr. Guajardo.

Compared with the general population, the team found higher rates of preterm births, neonatal ICU admissions, and premature membrane rupture, and infants that are small for gestational age. However, with the exception of the latter, all of these risks have been seen in pregnant women treated with other types of chemotherapy. “Perhaps it would be interesting to see if the incidence of small for gestational age neonates might be a bit higher in this population when compared to anthracycline-based therapy agents, but that does require a study that has a comparator group,” said Dr. Guajardo.

The researchers recruited 103 women with an average age of 34 years from 10 centers in 6 countries: United States, France, Spain, Mexico, Italy, and Costa Rica. The great majority were also treated with anthracyclines during gestation, and nearly all (97%) were treated with paclitaxel. The live birth rate was 98%, and 43.4% were preterm, 24% were small for gestational age, 16% were admitted to the neonate ICU, and 12.5% had hyperbilirubinemia.

Obstetric complications included intrauterine growth restriction (9%), preterm premature rupture of membranes (5%), gestational diabetes mellitus (5%), hypertensive disorders (4%), and pregnancy loss (2%).

After the presentation, Virginia Borges, MD, professor of medical oncology at University of Colorado Anschutz Medical Center, served as a discussant.

“Highlights of this study [include] that it is an international cohort from over six countries with over 100 cases of women included specifically focusing on the use of paclitaxel. They demonstrated safe outcomes for the pregnancies and the mothers,” Dr. Borges said during her presentation.

She went on to highlight several key points that physicians should consider when treating pregnancy-related breast cancer. “We want to achieve prepartum treatment wherever feasible to tackle that cancer before delivery of the child to prevent a pregnancy-related breast cancer from potentially turning into a postpartum breast cancer,” she said.

“If the tumor is ER+/HER2-, we now see we can safely give anthracyclines and taxanes from 12 to about 35 weeks of gestation. We don’t want to get too close to the delivery with chemotherapy. If a patient is HER2+, I prefer to give the anthracycline portion while the person is pregnant and then after delivery incorporate the taxane with the HER2 targeted therapies as there’s some older data showing concurrent therapy looks a bit better than sequential. In triple negative breast cancer, again I prefer to give the anthracycline and delay the taxane and carboplatin to overlap with immunotherapy so we are getting the necessary synergy there as well,” Dr. Borges added.

Dr. Guajardo has no relevant financial disclosures. Dr. Borges has consulted for SeaGen, Gilead, and AstraZeneca, and has received research funding from AstraZeneca, Gilead, Olema, and SeaGen.

SAN ANTONIO – Women aged 50 and over who have undergone curative treatment for breast cancer and remain cancer free after 3 years may safely de-escalate mammogram surveillance from the recommended annual schedule, according to results from a new randomized trial.

In the UK study, researchers found similar recurrence rates and overall survival between patients who continued to undergo annual screening versus women who underwent screening every 2 years after breast-conserving surgery or every 3 years after a mastectomy.

Current US guidelines recommend annual screening with no stopping point, while UK guidelines recommend annual screening for 5 years, followed by every 3 years after that.

The study was commissioned by the UK government after a previously commissioned systematic review showed lack of evidence for the existing frequency and duration of mammograms in this patient population, and a survey showed wide-ranging clinical practices. In response, the UK government funded the new study to evaluate whether it would be safe to reduce screening, according to Janet Dunn, PhD, who presented the study at the San Antonio Breast Cancer Symposium.

“Ladies are going back for years and years and years [for mammograms], and it’s inappropriate, it’s not necessary,” Dr. Dunn, professor of clinical trials and head of cancer trials at University of Warwick in the UK, said in an interview.

The lower frequency schedule requires that the patient be cancer free at 3 years following curative treatment. “We know for anybody going through breast cancer there are a couple of peaks of recurrence. One peak is 2 to 3 years [after curative treatment] for high-risk patients. The other peak is when they start hormone therapy, so at 5 to 6 years you get the peak. But this particular set of patients are at low to moderate risk, so they’re not the high-risk patients going into treatment trials,” said Dr. Dunn.

When asked if the findings should change practice, Dr. Dunn suggested that they could. “We would say that this is providing clinical evidence and probably changing guidance for the management of these patients: Instead of giving annual mammograms for years and years and years, after three years post curative surgery, and having gone through treatment with a baseline mammogram that’s clear, in the UK we can manage these patients back within the screening program, certainly for the mastectomy patients,” said Dr. Dunn.

She emphasized the potential mental health impact. “Women who are going through mammograms waiting for the results are much more anxious if they’ve had breast cancer before than those who were who were just going through normal screening. So [deescalation] is reducing anxiety. It’s also reducing the cost. It’s just reducing the burden on the whole health care system,” said Dr. Dunn.

During the Q&A session after the talk, Bruce Mann, MBBS, PhD, asked if there were differences in the pathology of the cancers that occurred in the less frequent group than those that arose in the annual group. If more frequent screening leads to earlier diagnosis of a tumor, “you would expect that those who have less [frequent screening] may be diagnosed with more advanced recurrences or new cancers, and that would eventually lead to a difference in outcome,” Dr. Mann said in an interview. He is director of breast cancer services at the Royal Melbourne Hospital in Australia.

He acknowledged the need to reconsider screening frequency, and complimented the researchers. “This is a nice pragmatic study. It’s interesting. It’s provocative. I think it’s a bit too early [to change practice]. I think we do need to see more information,” he said.

The researchers randomized 5235 women aged 50 and older to annual or less frequent mammography. The disease type was invasive in 87% of women, while 13% had ductal carcinoma in situ.

Over a median follow-up of 8.7 years, 7% experienced a recurrence. At 5 years, breast cancer–specific survival was 98.1% and 98.3% in the annual and less frequent groups, respectively (hazard ratio [HR], 0.92; 95% CI, 0.64-1.32). There was also no difference in recurrence-free survival or overall survival.

Analyses showed noninferiority of less frequent mammograms at a 3% margin (P < .0001) and a 1% margin (P = .003).

The researchers found that 83% of women were compliant with the mammogram schedule in the annual group, versus 69% in the less frequent arm. The COVID-19 pandemic was responsible for 35% of missed mammograms overall.

Quality of life measures showed that levels of distress over mammograms was similar across time and between the two groups, with 24% of women reporting medium or high levels of distress.

Dr. Dunn and Dr. Mann have no relevant financial disclosures.

SAN ANTONIO – Women aged 50 and over who have undergone curative treatment for breast cancer and remain cancer free after 3 years may safely de-escalate mammogram surveillance from the recommended annual schedule, according to results from a new randomized trial.

In the UK study, researchers found similar recurrence rates and overall survival between patients who continued to undergo annual screening versus women who underwent screening every 2 years after breast-conserving surgery or every 3 years after a mastectomy.

Current US guidelines recommend annual screening with no stopping point, while UK guidelines recommend annual screening for 5 years, followed by every 3 years after that.

The study was commissioned by the UK government after a previously commissioned systematic review showed lack of evidence for the existing frequency and duration of mammograms in this patient population, and a survey showed wide-ranging clinical practices. In response, the UK government funded the new study to evaluate whether it would be safe to reduce screening, according to Janet Dunn, PhD, who presented the study at the San Antonio Breast Cancer Symposium.

“Ladies are going back for years and years and years [for mammograms], and it’s inappropriate, it’s not necessary,” Dr. Dunn, professor of clinical trials and head of cancer trials at University of Warwick in the UK, said in an interview.

The lower frequency schedule requires that the patient be cancer free at 3 years following curative treatment. “We know for anybody going through breast cancer there are a couple of peaks of recurrence. One peak is 2 to 3 years [after curative treatment] for high-risk patients. The other peak is when they start hormone therapy, so at 5 to 6 years you get the peak. But this particular set of patients are at low to moderate risk, so they’re not the high-risk patients going into treatment trials,” said Dr. Dunn.

When asked if the findings should change practice, Dr. Dunn suggested that they could. “We would say that this is providing clinical evidence and probably changing guidance for the management of these patients: Instead of giving annual mammograms for years and years and years, after three years post curative surgery, and having gone through treatment with a baseline mammogram that’s clear, in the UK we can manage these patients back within the screening program, certainly for the mastectomy patients,” said Dr. Dunn.

She emphasized the potential mental health impact. “Women who are going through mammograms waiting for the results are much more anxious if they’ve had breast cancer before than those who were who were just going through normal screening. So [deescalation] is reducing anxiety. It’s also reducing the cost. It’s just reducing the burden on the whole health care system,” said Dr. Dunn.

During the Q&A session after the talk, Bruce Mann, MBBS, PhD, asked if there were differences in the pathology of the cancers that occurred in the less frequent group than those that arose in the annual group. If more frequent screening leads to earlier diagnosis of a tumor, “you would expect that those who have less [frequent screening] may be diagnosed with more advanced recurrences or new cancers, and that would eventually lead to a difference in outcome,” Dr. Mann said in an interview. He is director of breast cancer services at the Royal Melbourne Hospital in Australia.

He acknowledged the need to reconsider screening frequency, and complimented the researchers. “This is a nice pragmatic study. It’s interesting. It’s provocative. I think it’s a bit too early [to change practice]. I think we do need to see more information,” he said.

The researchers randomized 5235 women aged 50 and older to annual or less frequent mammography. The disease type was invasive in 87% of women, while 13% had ductal carcinoma in situ.

Over a median follow-up of 8.7 years, 7% experienced a recurrence. At 5 years, breast cancer–specific survival was 98.1% and 98.3% in the annual and less frequent groups, respectively (hazard ratio [HR], 0.92; 95% CI, 0.64-1.32). There was also no difference in recurrence-free survival or overall survival.

Analyses showed noninferiority of less frequent mammograms at a 3% margin (P < .0001) and a 1% margin (P = .003).

The researchers found that 83% of women were compliant with the mammogram schedule in the annual group, versus 69% in the less frequent arm. The COVID-19 pandemic was responsible for 35% of missed mammograms overall.

Quality of life measures showed that levels of distress over mammograms was similar across time and between the two groups, with 24% of women reporting medium or high levels of distress.

Dr. Dunn and Dr. Mann have no relevant financial disclosures.

SAN ANTONIO – Women aged 50 and over who have undergone curative treatment for breast cancer and remain cancer free after 3 years may safely de-escalate mammogram surveillance from the recommended annual schedule, according to results from a new randomized trial.

In the UK study, researchers found similar recurrence rates and overall survival between patients who continued to undergo annual screening versus women who underwent screening every 2 years after breast-conserving surgery or every 3 years after a mastectomy.

Current US guidelines recommend annual screening with no stopping point, while UK guidelines recommend annual screening for 5 years, followed by every 3 years after that.

The study was commissioned by the UK government after a previously commissioned systematic review showed lack of evidence for the existing frequency and duration of mammograms in this patient population, and a survey showed wide-ranging clinical practices. In response, the UK government funded the new study to evaluate whether it would be safe to reduce screening, according to Janet Dunn, PhD, who presented the study at the San Antonio Breast Cancer Symposium.

“Ladies are going back for years and years and years [for mammograms], and it’s inappropriate, it’s not necessary,” Dr. Dunn, professor of clinical trials and head of cancer trials at University of Warwick in the UK, said in an interview.

The lower frequency schedule requires that the patient be cancer free at 3 years following curative treatment. “We know for anybody going through breast cancer there are a couple of peaks of recurrence. One peak is 2 to 3 years [after curative treatment] for high-risk patients. The other peak is when they start hormone therapy, so at 5 to 6 years you get the peak. But this particular set of patients are at low to moderate risk, so they’re not the high-risk patients going into treatment trials,” said Dr. Dunn.

When asked if the findings should change practice, Dr. Dunn suggested that they could. “We would say that this is providing clinical evidence and probably changing guidance for the management of these patients: Instead of giving annual mammograms for years and years and years, after three years post curative surgery, and having gone through treatment with a baseline mammogram that’s clear, in the UK we can manage these patients back within the screening program, certainly for the mastectomy patients,” said Dr. Dunn.

She emphasized the potential mental health impact. “Women who are going through mammograms waiting for the results are much more anxious if they’ve had breast cancer before than those who were who were just going through normal screening. So [deescalation] is reducing anxiety. It’s also reducing the cost. It’s just reducing the burden on the whole health care system,” said Dr. Dunn.

During the Q&A session after the talk, Bruce Mann, MBBS, PhD, asked if there were differences in the pathology of the cancers that occurred in the less frequent group than those that arose in the annual group. If more frequent screening leads to earlier diagnosis of a tumor, “you would expect that those who have less [frequent screening] may be diagnosed with more advanced recurrences or new cancers, and that would eventually lead to a difference in outcome,” Dr. Mann said in an interview. He is director of breast cancer services at the Royal Melbourne Hospital in Australia.

He acknowledged the need to reconsider screening frequency, and complimented the researchers. “This is a nice pragmatic study. It’s interesting. It’s provocative. I think it’s a bit too early [to change practice]. I think we do need to see more information,” he said.

The researchers randomized 5235 women aged 50 and older to annual or less frequent mammography. The disease type was invasive in 87% of women, while 13% had ductal carcinoma in situ.

Over a median follow-up of 8.7 years, 7% experienced a recurrence. At 5 years, breast cancer–specific survival was 98.1% and 98.3% in the annual and less frequent groups, respectively (hazard ratio [HR], 0.92; 95% CI, 0.64-1.32). There was also no difference in recurrence-free survival or overall survival.

Analyses showed noninferiority of less frequent mammograms at a 3% margin (P < .0001) and a 1% margin (P = .003).

The researchers found that 83% of women were compliant with the mammogram schedule in the annual group, versus 69% in the less frequent arm. The COVID-19 pandemic was responsible for 35% of missed mammograms overall.

Quality of life measures showed that levels of distress over mammograms was similar across time and between the two groups, with 24% of women reporting medium or high levels of distress.

Dr. Dunn and Dr. Mann have no relevant financial disclosures.

SAN ANTONIO — In endocrine-resistant, HR+/HER2- metastatic breast cancer, the antibody-drug conjugate (ADC) datopotamab deruxtecan (dato-DXd, Daiichi Sankyo/AstraZeneca) has greater efficacy and a better safety profile than investigator-chosen chemotherapy, according to the latest results from the TROPION-Breast01 clinical trial.

If approved, the ADC would join sacituzumab govitecan (Trodelvy, Gilead) as agents that target trophoblast cell-surface antigen-2 (Trop-2), which is universally expressed in breast cancer, according to Aditya Bardia, MD, who presented the new results at the San Antonio Breast Cancer Symposium.

“Dato-DXd not only showed improvement in efficacy [versus chemotherapy], but had a favorable safety profile and a favorable quality of life profile as compared to standard chemotherapy. If this drug gets approved, we need more work in terms of biomarkers of response and resistance to understand how to select these agents and how to sequence these different agents,” Dr. Bardia said in an interview. He is associate professor of medicine at Harvard Medical School and Massachusetts General Hospital Cancer Center.

Dato-DXd has a proprietary linker technology that makes it more stable in plasma and more selective for tumor cells, where overexpressed enzymes cleave it and lead to release of the drug. This reduces off-target toxicity, said Dr. Bardia.

The primary results from TROPION-Breast01, presented at ESMO 2023, showed statistically significant improvement in progression-free survival compared to investigator’s choice of chemotherapy (hazard ratio, [HR], 0.63; P < .0001) and a higher overall response rate (36.4% versus 22.9%).

At SABCS, Dr. Bardia presented additional PFS sub-analyses and safety data.

TROPION-Breast01 included 732 patients who had failed or were ineligible for endocrine therapy, and who had received 1-2 lines of chemotherapy in the metastatic or inoperable setting. They were randomized to dato-DXd or chemotherapy.

The median PFS as determined by blinded independent central review was longer in the dato-DXd group (6.9 versus 4.5 months; P < .0001). Time to first subsequent therapy was also longer (median 8.2 versus 5.0 months; HR, 0.53; 95% CI, 0.45-0.64).

PFS benefit was similar regardless of duration of previous CDK4/6 inhibitor treatment. There was no significant difference in median PFS among patients with brain metastases at baseline (HR, 0.73; 95% CI, 0.39-1.42).

Grade 3 or higher treatment-related adverse events were less common in the dato-DXd group (21% versus 45%), as were the incidences of dose interruption (12% versus 25%), treatment-related neutropenia (11% versus 42%), grade 3 or higher treatment-related neutropenia (1% versus 31%), neutropenia-related dose interruption (0% versus 17%), and neutropenia-related dose reduction (0.3% versus 13%). G-CSF usage was lower in the dato-DXd group during treatment (3% versus 22%) and after treatment (0.3% versus 8%).

Stomatitis was more common in the dato-DXd group (50% versus 13%), including grade 3 (6% versus 3%). Dose reduction due to stomatitis was also more common (12% versus 1%), and discontinuation occurred in just 1 patient (0.3%) in the dato-DXd group.

The median time to confirmed deterioration, as measured by the Global Health Status/Quality of Life scale, was longer in the dato-DXd group (9.0 versus 4.8 months; HR, 0.76; 95% CI, 0.58-0.98).

During the Q & A period after the talk, Marc E. Lippman, MD, professor of oncology and director of the breast cancer program at Georgetown University’s Lombardi Comprehensive Cancer Center, questioned the assumption that Trop-2 is universally expressed in breast cancer, and asked if there were any data on outcomes associated with its expression. “That’s a very good question,” said Dr. Bardia. He said that the team is working on the problem, including identifying the best tool to measure Trop-2 expression, but also addressing whether expression changes over time. Finally, the team hopes to determine if treatment response might relate to levels of expression.

Trop-2 expression was studied in the ASCENT trial that examined sacituzumab govitecan in metastatic triple-negative breast cancer, and there was no apparent link. “In general, we don’t see a very strong correlation between Trop-2 expression and outcomes. In the ASCENT trial, even in patients who had low expression of Trop-2, the outcomes with Trop-2 antibody drug conjugates [were] superior to standard chemotherapy,” replied Dr. Bardia.

Ron Bose, MD, PhD, also asked if there would be broader biomarker analyses of responders versus nonresponders to dato-dxd. “I think it’s very important to know, what are the biomarkers that predict efficacy for dato-dxd. The median progression free survival improvement was only about two months, maybe a little bit more, so knowing which patients are going to get the most benefit will be very important,” Dr. Bose said in an interview. Dr. Bose is associate professor of oncology at the Washington University School of Medicine in St. Louis.

Overall, he was impressed by the results. “The median progression free survival benefit is moderate, but the safety I think is really particularly strong, and when I’m thinking about this for my patients, the fact that there is a progression free survival benefit, plus a safety benefit [compared to chemotherapy] makes it very appealing,” he said.

Dr. Bose has consulted for Genentech. Dr. Bardia has been on advisory boards for Pfizer, Novartis, Genentech, Merck, Radius Health/Menarini, Immunomedics/Gilead, Sanofi, Daiichi Pharma/AstraZeneca, Phillips, Eli Lilly, Mersana, and Foundation Medicine. He has received research grants from Genentech, Novartis, Pfizer, Merck, Sanofi, Radius Health/Menarini, Immunomedics/Gilead, Daiichi Pharma/AstraZeneca, Natera, and Eli Lilly.

SAN ANTONIO — In endocrine-resistant, HR+/HER2- metastatic breast cancer, the antibody-drug conjugate (ADC) datopotamab deruxtecan (dato-DXd, Daiichi Sankyo/AstraZeneca) has greater efficacy and a better safety profile than investigator-chosen chemotherapy, according to the latest results from the TROPION-Breast01 clinical trial.

If approved, the ADC would join sacituzumab govitecan (Trodelvy, Gilead) as agents that target trophoblast cell-surface antigen-2 (Trop-2), which is universally expressed in breast cancer, according to Aditya Bardia, MD, who presented the new results at the San Antonio Breast Cancer Symposium.

“Dato-DXd not only showed improvement in efficacy [versus chemotherapy], but had a favorable safety profile and a favorable quality of life profile as compared to standard chemotherapy. If this drug gets approved, we need more work in terms of biomarkers of response and resistance to understand how to select these agents and how to sequence these different agents,” Dr. Bardia said in an interview. He is associate professor of medicine at Harvard Medical School and Massachusetts General Hospital Cancer Center.

Dato-DXd has a proprietary linker technology that makes it more stable in plasma and more selective for tumor cells, where overexpressed enzymes cleave it and lead to release of the drug. This reduces off-target toxicity, said Dr. Bardia.

The primary results from TROPION-Breast01, presented at ESMO 2023, showed statistically significant improvement in progression-free survival compared to investigator’s choice of chemotherapy (hazard ratio, [HR], 0.63; P < .0001) and a higher overall response rate (36.4% versus 22.9%).

At SABCS, Dr. Bardia presented additional PFS sub-analyses and safety data.

TROPION-Breast01 included 732 patients who had failed or were ineligible for endocrine therapy, and who had received 1-2 lines of chemotherapy in the metastatic or inoperable setting. They were randomized to dato-DXd or chemotherapy.

The median PFS as determined by blinded independent central review was longer in the dato-DXd group (6.9 versus 4.5 months; P < .0001). Time to first subsequent therapy was also longer (median 8.2 versus 5.0 months; HR, 0.53; 95% CI, 0.45-0.64).

PFS benefit was similar regardless of duration of previous CDK4/6 inhibitor treatment. There was no significant difference in median PFS among patients with brain metastases at baseline (HR, 0.73; 95% CI, 0.39-1.42).

Grade 3 or higher treatment-related adverse events were less common in the dato-DXd group (21% versus 45%), as were the incidences of dose interruption (12% versus 25%), treatment-related neutropenia (11% versus 42%), grade 3 or higher treatment-related neutropenia (1% versus 31%), neutropenia-related dose interruption (0% versus 17%), and neutropenia-related dose reduction (0.3% versus 13%). G-CSF usage was lower in the dato-DXd group during treatment (3% versus 22%) and after treatment (0.3% versus 8%).

Stomatitis was more common in the dato-DXd group (50% versus 13%), including grade 3 (6% versus 3%). Dose reduction due to stomatitis was also more common (12% versus 1%), and discontinuation occurred in just 1 patient (0.3%) in the dato-DXd group.

The median time to confirmed deterioration, as measured by the Global Health Status/Quality of Life scale, was longer in the dato-DXd group (9.0 versus 4.8 months; HR, 0.76; 95% CI, 0.58-0.98).

During the Q & A period after the talk, Marc E. Lippman, MD, professor of oncology and director of the breast cancer program at Georgetown University’s Lombardi Comprehensive Cancer Center, questioned the assumption that Trop-2 is universally expressed in breast cancer, and asked if there were any data on outcomes associated with its expression. “That’s a very good question,” said Dr. Bardia. He said that the team is working on the problem, including identifying the best tool to measure Trop-2 expression, but also addressing whether expression changes over time. Finally, the team hopes to determine if treatment response might relate to levels of expression.

Trop-2 expression was studied in the ASCENT trial that examined sacituzumab govitecan in metastatic triple-negative breast cancer, and there was no apparent link. “In general, we don’t see a very strong correlation between Trop-2 expression and outcomes. In the ASCENT trial, even in patients who had low expression of Trop-2, the outcomes with Trop-2 antibody drug conjugates [were] superior to standard chemotherapy,” replied Dr. Bardia.

Ron Bose, MD, PhD, also asked if there would be broader biomarker analyses of responders versus nonresponders to dato-dxd. “I think it’s very important to know, what are the biomarkers that predict efficacy for dato-dxd. The median progression free survival improvement was only about two months, maybe a little bit more, so knowing which patients are going to get the most benefit will be very important,” Dr. Bose said in an interview. Dr. Bose is associate professor of oncology at the Washington University School of Medicine in St. Louis.

Overall, he was impressed by the results. “The median progression free survival benefit is moderate, but the safety I think is really particularly strong, and when I’m thinking about this for my patients, the fact that there is a progression free survival benefit, plus a safety benefit [compared to chemotherapy] makes it very appealing,” he said.

Dr. Bose has consulted for Genentech. Dr. Bardia has been on advisory boards for Pfizer, Novartis, Genentech, Merck, Radius Health/Menarini, Immunomedics/Gilead, Sanofi, Daiichi Pharma/AstraZeneca, Phillips, Eli Lilly, Mersana, and Foundation Medicine. He has received research grants from Genentech, Novartis, Pfizer, Merck, Sanofi, Radius Health/Menarini, Immunomedics/Gilead, Daiichi Pharma/AstraZeneca, Natera, and Eli Lilly.

SAN ANTONIO — In endocrine-resistant, HR+/HER2- metastatic breast cancer, the antibody-drug conjugate (ADC) datopotamab deruxtecan (dato-DXd, Daiichi Sankyo/AstraZeneca) has greater efficacy and a better safety profile than investigator-chosen chemotherapy, according to the latest results from the TROPION-Breast01 clinical trial.

If approved, the ADC would join sacituzumab govitecan (Trodelvy, Gilead) as agents that target trophoblast cell-surface antigen-2 (Trop-2), which is universally expressed in breast cancer, according to Aditya Bardia, MD, who presented the new results at the San Antonio Breast Cancer Symposium.

“Dato-DXd not only showed improvement in efficacy [versus chemotherapy], but had a favorable safety profile and a favorable quality of life profile as compared to standard chemotherapy. If this drug gets approved, we need more work in terms of biomarkers of response and resistance to understand how to select these agents and how to sequence these different agents,” Dr. Bardia said in an interview. He is associate professor of medicine at Harvard Medical School and Massachusetts General Hospital Cancer Center.

Dato-DXd has a proprietary linker technology that makes it more stable in plasma and more selective for tumor cells, where overexpressed enzymes cleave it and lead to release of the drug. This reduces off-target toxicity, said Dr. Bardia.

The primary results from TROPION-Breast01, presented at ESMO 2023, showed statistically significant improvement in progression-free survival compared to investigator’s choice of chemotherapy (hazard ratio, [HR], 0.63; P < .0001) and a higher overall response rate (36.4% versus 22.9%).

At SABCS, Dr. Bardia presented additional PFS sub-analyses and safety data.

TROPION-Breast01 included 732 patients who had failed or were ineligible for endocrine therapy, and who had received 1-2 lines of chemotherapy in the metastatic or inoperable setting. They were randomized to dato-DXd or chemotherapy.

The median PFS as determined by blinded independent central review was longer in the dato-DXd group (6.9 versus 4.5 months; P < .0001). Time to first subsequent therapy was also longer (median 8.2 versus 5.0 months; HR, 0.53; 95% CI, 0.45-0.64).

PFS benefit was similar regardless of duration of previous CDK4/6 inhibitor treatment. There was no significant difference in median PFS among patients with brain metastases at baseline (HR, 0.73; 95% CI, 0.39-1.42).

Grade 3 or higher treatment-related adverse events were less common in the dato-DXd group (21% versus 45%), as were the incidences of dose interruption (12% versus 25%), treatment-related neutropenia (11% versus 42%), grade 3 or higher treatment-related neutropenia (1% versus 31%), neutropenia-related dose interruption (0% versus 17%), and neutropenia-related dose reduction (0.3% versus 13%). G-CSF usage was lower in the dato-DXd group during treatment (3% versus 22%) and after treatment (0.3% versus 8%).

Stomatitis was more common in the dato-DXd group (50% versus 13%), including grade 3 (6% versus 3%). Dose reduction due to stomatitis was also more common (12% versus 1%), and discontinuation occurred in just 1 patient (0.3%) in the dato-DXd group.

The median time to confirmed deterioration, as measured by the Global Health Status/Quality of Life scale, was longer in the dato-DXd group (9.0 versus 4.8 months; HR, 0.76; 95% CI, 0.58-0.98).

During the Q & A period after the talk, Marc E. Lippman, MD, professor of oncology and director of the breast cancer program at Georgetown University’s Lombardi Comprehensive Cancer Center, questioned the assumption that Trop-2 is universally expressed in breast cancer, and asked if there were any data on outcomes associated with its expression. “That’s a very good question,” said Dr. Bardia. He said that the team is working on the problem, including identifying the best tool to measure Trop-2 expression, but also addressing whether expression changes over time. Finally, the team hopes to determine if treatment response might relate to levels of expression.

Trop-2 expression was studied in the ASCENT trial that examined sacituzumab govitecan in metastatic triple-negative breast cancer, and there was no apparent link. “In general, we don’t see a very strong correlation between Trop-2 expression and outcomes. In the ASCENT trial, even in patients who had low expression of Trop-2, the outcomes with Trop-2 antibody drug conjugates [were] superior to standard chemotherapy,” replied Dr. Bardia.

Ron Bose, MD, PhD, also asked if there would be broader biomarker analyses of responders versus nonresponders to dato-dxd. “I think it’s very important to know, what are the biomarkers that predict efficacy for dato-dxd. The median progression free survival improvement was only about two months, maybe a little bit more, so knowing which patients are going to get the most benefit will be very important,” Dr. Bose said in an interview. Dr. Bose is associate professor of oncology at the Washington University School of Medicine in St. Louis.

Overall, he was impressed by the results. “The median progression free survival benefit is moderate, but the safety I think is really particularly strong, and when I’m thinking about this for my patients, the fact that there is a progression free survival benefit, plus a safety benefit [compared to chemotherapy] makes it very appealing,” he said.

Dr. Bose has consulted for Genentech. Dr. Bardia has been on advisory boards for Pfizer, Novartis, Genentech, Merck, Radius Health/Menarini, Immunomedics/Gilead, Sanofi, Daiichi Pharma/AstraZeneca, Phillips, Eli Lilly, Mersana, and Foundation Medicine. He has received research grants from Genentech, Novartis, Pfizer, Merck, Sanofi, Radius Health/Menarini, Immunomedics/Gilead, Daiichi Pharma/AstraZeneca, Natera, and Eli Lilly.

SAN ANTONIO – In previously treated patients with locally advanced unresectable or metastatic HER2-positive breast cancer, tucatinib (Tukysa, Seagen) and trastuzumab emtansine (Kadcyla, T-DM1, Genentech) improved progression-free survival (PFS) versus T-DM1 alone, according to results from the phase III HER2CLIMB-02 study. A subanalysis of patients with brain metastases at baseline also showed an improvement in this population.

Brain metastases are common HER2+ breast cancer, and this is associated with poor outcomes, according to Sara A. Hurvitz, MD, who presented the study at the San Antonio Breast Cancer Symposium. There are few treatment options available for this population.

“Adding tucatinib to TDM-1 significantly improved progression free survival in patients with previously treated HER2+ advanced disease. The types of adverse events were consistent with previous reporting, and this is the second randomized study which included patients with brain metastases to demonstrate that a tucatinib-based regimen delays disease progression in this disease setting,” said Dr. Hurvitz, professor and head of the division of hematology and oncology at the University of Washington Department of Medicine and senior vice president and director of the Clinical Research Division at Fred Hutchinson Cancer Center.

Both tucatinib and TDM-1 target the HER2 receptor. T-DM1 is an antibody-drug conjugate (ADC) of trastuzumab (Herceptin) and the drug emtansine that has received FDA approval as monotherapy for both early- and late-stage HER2-positive breast cancer. Tucatinib is a small-molecule HER2 inhibitor and has efficacy against disease progression in the central nervous system, which is unusual among HER2-targeted therapies.

The earlier HER2CLIMB trial showed improved outcomes among heavily pretreated patients — including those with brain metastases — when tucatinib was added to trastuzumab and capecitabine (Xeloda, Genentech). In 2020, the FDA approved the combination for advanced unresectable or metastatic HER2-positive breast cancer, including brain metastases.

To determine if tucatinib could also improve responses when combined with a trastuzumab-based ADC, the researchers randomized 463 patients to tucatinib plus T-DM1 or placebo plus T-DM1. Nearly half (44.1%) of patients had brain metastases at baseline. Over a median follow-up of 24.4 months, the combination group had a 24% lower risk of progression or death (hazard ratio [HR], 0.76; P = .0163) and a longer median progression-free survival (9.5 months versus 7.4 months).

The PFS benefit was also seen in patients with baseline brain metastases (HR, 0.64; 95% CI, 0.46-0.89]). An insufficient number of survival events had occurred at the interim analysis to determine OS at the time of the presentation.

There was no statistically significant difference in overall response rate in the intervention arm. Treatment-emergent adverse events (TEAEs) that were more common in the tucatinib arm included nausea (65.4% vs. 49.4%), diarrhea (56.7% vs. 26.6%), and fatigue (48.9% vs. 37.3%). Grade 3 or higher TEAEs in the tucatinib arm included alanine and aspartate aminotransferase elevations (16.5% for both), versus 2.6% in the control arm for both. TEAEs associated treatment discontinuation occurred among 22.1% in the tucatinib arm and 11.6% in the control arm. TEAEs that led to mortality occurred in 1.3% of the tucatinib group and 0.9% of the control arm.

“I think tucatinib really does contain level one evidence for use in the setting of CNS metastases. There’s not yet data that has replaced that, so I will continue to consider using it in the second line setting, as it’s currently indicated in the presence of brain metastases. Without brain metastases, based on [the DESTINY-Breast03 trial], I’d probably opt for [trastuzumab deroxtecan], which is still the standard,” said Dr. Hurvitz.

Following the talk, Valentina Guarneri, MD, PhD, served as a discussant. She underscored the clinical need for treatment of patients with brain metastases.

“Brain metastases represent a devastating event for our patients and remain an unmet need considering that all of these patients will eventually require local therapies, with potentially debilitating sequelae. Since optimal therapy for these patients should not be an afterthought, clinical trials taking the risk of including these patients must be valued,” said Dr. Guarneri, professor of oncology at the University of Padua in Italy.

She acknowledged the success of the dual HER2 inhibitor strategy, and said it opens up avenues for combinations with novel antibody-drug conjugates. “HER2CLIMB-02 is unlikely to change the current algorithm, but it reinforces the role of tucatinib in the treatment of HER2+ metastatic breast cancer. The data further support studies in the early disease setting aiming to prevent the development of brain metastases,” said Dr. Guarneri.

The study was funded by Seagen. Dr. Hurvitz has received research funding from Ambrx, Arvinas, AstraZeneca, Bayer, Celcuity, CytomX Therapeutics, Daiichi Sankyo, Dantari Inc., Dignitana, Genentech, (Roche), G1 Therapeutics, Gilead Sciences Inc., Greenwich LifeSciences Inc., GSK, Immunomedics, Eli Lilly and Company, Loxo Oncology, MacroGenics, Novartis, OBI Pharma Inc., Orinove Inc., Orum Therapeutics, Pfizer, Phoenix Molecular Designs, Pieris Pharmaceuticals Inc., Puma Biotechnology, Radius Health, Sanofi, Seagen, and Zymeworks; has received royalties from McGraw Hill, Sage Publications, Wiley, and Wolters Kluwer; has served on the data and safety monitoring board for Alliance Foundation Trials LLC, Atossa Therapeutics, and the Quantum Leap Healthcare Collaborative; and has received honoraria from the Vaniam Group and OncLive. Her husband holds stock in ROMTech. Dr. Guarneri has been a member of the advisory boards for AstraZeneca, Daiichi Sankyo, Eisai, Eli Lilly, Exact Sciences, Gilead, Merck Serono, MSD, Novartis, Pfizer, Olema Oncology, and Pierre Fabre. She has been an invited speaker for AstraZeneca, Daiichi Sankyo, Eli Lilly, Exact Sciences, Gilead, GSK Novartis, and Zentiva.

SAN ANTONIO – In previously treated patients with locally advanced unresectable or metastatic HER2-positive breast cancer, tucatinib (Tukysa, Seagen) and trastuzumab emtansine (Kadcyla, T-DM1, Genentech) improved progression-free survival (PFS) versus T-DM1 alone, according to results from the phase III HER2CLIMB-02 study. A subanalysis of patients with brain metastases at baseline also showed an improvement in this population.

Brain metastases are common HER2+ breast cancer, and this is associated with poor outcomes, according to Sara A. Hurvitz, MD, who presented the study at the San Antonio Breast Cancer Symposium. There are few treatment options available for this population.

“Adding tucatinib to TDM-1 significantly improved progression free survival in patients with previously treated HER2+ advanced disease. The types of adverse events were consistent with previous reporting, and this is the second randomized study which included patients with brain metastases to demonstrate that a tucatinib-based regimen delays disease progression in this disease setting,” said Dr. Hurvitz, professor and head of the division of hematology and oncology at the University of Washington Department of Medicine and senior vice president and director of the Clinical Research Division at Fred Hutchinson Cancer Center.

Both tucatinib and TDM-1 target the HER2 receptor. T-DM1 is an antibody-drug conjugate (ADC) of trastuzumab (Herceptin) and the drug emtansine that has received FDA approval as monotherapy for both early- and late-stage HER2-positive breast cancer. Tucatinib is a small-molecule HER2 inhibitor and has efficacy against disease progression in the central nervous system, which is unusual among HER2-targeted therapies.

The earlier HER2CLIMB trial showed improved outcomes among heavily pretreated patients — including those with brain metastases — when tucatinib was added to trastuzumab and capecitabine (Xeloda, Genentech). In 2020, the FDA approved the combination for advanced unresectable or metastatic HER2-positive breast cancer, including brain metastases.

To determine if tucatinib could also improve responses when combined with a trastuzumab-based ADC, the researchers randomized 463 patients to tucatinib plus T-DM1 or placebo plus T-DM1. Nearly half (44.1%) of patients had brain metastases at baseline. Over a median follow-up of 24.4 months, the combination group had a 24% lower risk of progression or death (hazard ratio [HR], 0.76; P = .0163) and a longer median progression-free survival (9.5 months versus 7.4 months).

The PFS benefit was also seen in patients with baseline brain metastases (HR, 0.64; 95% CI, 0.46-0.89]). An insufficient number of survival events had occurred at the interim analysis to determine OS at the time of the presentation.

There was no statistically significant difference in overall response rate in the intervention arm. Treatment-emergent adverse events (TEAEs) that were more common in the tucatinib arm included nausea (65.4% vs. 49.4%), diarrhea (56.7% vs. 26.6%), and fatigue (48.9% vs. 37.3%). Grade 3 or higher TEAEs in the tucatinib arm included alanine and aspartate aminotransferase elevations (16.5% for both), versus 2.6% in the control arm for both. TEAEs associated treatment discontinuation occurred among 22.1% in the tucatinib arm and 11.6% in the control arm. TEAEs that led to mortality occurred in 1.3% of the tucatinib group and 0.9% of the control arm.

“I think tucatinib really does contain level one evidence for use in the setting of CNS metastases. There’s not yet data that has replaced that, so I will continue to consider using it in the second line setting, as it’s currently indicated in the presence of brain metastases. Without brain metastases, based on [the DESTINY-Breast03 trial], I’d probably opt for [trastuzumab deroxtecan], which is still the standard,” said Dr. Hurvitz.

Following the talk, Valentina Guarneri, MD, PhD, served as a discussant. She underscored the clinical need for treatment of patients with brain metastases.

“Brain metastases represent a devastating event for our patients and remain an unmet need considering that all of these patients will eventually require local therapies, with potentially debilitating sequelae. Since optimal therapy for these patients should not be an afterthought, clinical trials taking the risk of including these patients must be valued,” said Dr. Guarneri, professor of oncology at the University of Padua in Italy.

She acknowledged the success of the dual HER2 inhibitor strategy, and said it opens up avenues for combinations with novel antibody-drug conjugates. “HER2CLIMB-02 is unlikely to change the current algorithm, but it reinforces the role of tucatinib in the treatment of HER2+ metastatic breast cancer. The data further support studies in the early disease setting aiming to prevent the development of brain metastases,” said Dr. Guarneri.

The study was funded by Seagen. Dr. Hurvitz has received research funding from Ambrx, Arvinas, AstraZeneca, Bayer, Celcuity, CytomX Therapeutics, Daiichi Sankyo, Dantari Inc., Dignitana, Genentech, (Roche), G1 Therapeutics, Gilead Sciences Inc., Greenwich LifeSciences Inc., GSK, Immunomedics, Eli Lilly and Company, Loxo Oncology, MacroGenics, Novartis, OBI Pharma Inc., Orinove Inc., Orum Therapeutics, Pfizer, Phoenix Molecular Designs, Pieris Pharmaceuticals Inc., Puma Biotechnology, Radius Health, Sanofi, Seagen, and Zymeworks; has received royalties from McGraw Hill, Sage Publications, Wiley, and Wolters Kluwer; has served on the data and safety monitoring board for Alliance Foundation Trials LLC, Atossa Therapeutics, and the Quantum Leap Healthcare Collaborative; and has received honoraria from the Vaniam Group and OncLive. Her husband holds stock in ROMTech. Dr. Guarneri has been a member of the advisory boards for AstraZeneca, Daiichi Sankyo, Eisai, Eli Lilly, Exact Sciences, Gilead, Merck Serono, MSD, Novartis, Pfizer, Olema Oncology, and Pierre Fabre. She has been an invited speaker for AstraZeneca, Daiichi Sankyo, Eli Lilly, Exact Sciences, Gilead, GSK Novartis, and Zentiva.

SAN ANTONIO – In previously treated patients with locally advanced unresectable or metastatic HER2-positive breast cancer, tucatinib (Tukysa, Seagen) and trastuzumab emtansine (Kadcyla, T-DM1, Genentech) improved progression-free survival (PFS) versus T-DM1 alone, according to results from the phase III HER2CLIMB-02 study. A subanalysis of patients with brain metastases at baseline also showed an improvement in this population.

Brain metastases are common HER2+ breast cancer, and this is associated with poor outcomes, according to Sara A. Hurvitz, MD, who presented the study at the San Antonio Breast Cancer Symposium. There are few treatment options available for this population.

“Adding tucatinib to TDM-1 significantly improved progression free survival in patients with previously treated HER2+ advanced disease. The types of adverse events were consistent with previous reporting, and this is the second randomized study which included patients with brain metastases to demonstrate that a tucatinib-based regimen delays disease progression in this disease setting,” said Dr. Hurvitz, professor and head of the division of hematology and oncology at the University of Washington Department of Medicine and senior vice president and director of the Clinical Research Division at Fred Hutchinson Cancer Center.

Both tucatinib and TDM-1 target the HER2 receptor. T-DM1 is an antibody-drug conjugate (ADC) of trastuzumab (Herceptin) and the drug emtansine that has received FDA approval as monotherapy for both early- and late-stage HER2-positive breast cancer. Tucatinib is a small-molecule HER2 inhibitor and has efficacy against disease progression in the central nervous system, which is unusual among HER2-targeted therapies.

The earlier HER2CLIMB trial showed improved outcomes among heavily pretreated patients — including those with brain metastases — when tucatinib was added to trastuzumab and capecitabine (Xeloda, Genentech). In 2020, the FDA approved the combination for advanced unresectable or metastatic HER2-positive breast cancer, including brain metastases.

To determine if tucatinib could also improve responses when combined with a trastuzumab-based ADC, the researchers randomized 463 patients to tucatinib plus T-DM1 or placebo plus T-DM1. Nearly half (44.1%) of patients had brain metastases at baseline. Over a median follow-up of 24.4 months, the combination group had a 24% lower risk of progression or death (hazard ratio [HR], 0.76; P = .0163) and a longer median progression-free survival (9.5 months versus 7.4 months).

The PFS benefit was also seen in patients with baseline brain metastases (HR, 0.64; 95% CI, 0.46-0.89]). An insufficient number of survival events had occurred at the interim analysis to determine OS at the time of the presentation.

There was no statistically significant difference in overall response rate in the intervention arm. Treatment-emergent adverse events (TEAEs) that were more common in the tucatinib arm included nausea (65.4% vs. 49.4%), diarrhea (56.7% vs. 26.6%), and fatigue (48.9% vs. 37.3%). Grade 3 or higher TEAEs in the tucatinib arm included alanine and aspartate aminotransferase elevations (16.5% for both), versus 2.6% in the control arm for both. TEAEs associated treatment discontinuation occurred among 22.1% in the tucatinib arm and 11.6% in the control arm. TEAEs that led to mortality occurred in 1.3% of the tucatinib group and 0.9% of the control arm.

“I think tucatinib really does contain level one evidence for use in the setting of CNS metastases. There’s not yet data that has replaced that, so I will continue to consider using it in the second line setting, as it’s currently indicated in the presence of brain metastases. Without brain metastases, based on [the DESTINY-Breast03 trial], I’d probably opt for [trastuzumab deroxtecan], which is still the standard,” said Dr. Hurvitz.

Following the talk, Valentina Guarneri, MD, PhD, served as a discussant. She underscored the clinical need for treatment of patients with brain metastases.

“Brain metastases represent a devastating event for our patients and remain an unmet need considering that all of these patients will eventually require local therapies, with potentially debilitating sequelae. Since optimal therapy for these patients should not be an afterthought, clinical trials taking the risk of including these patients must be valued,” said Dr. Guarneri, professor of oncology at the University of Padua in Italy.

She acknowledged the success of the dual HER2 inhibitor strategy, and said it opens up avenues for combinations with novel antibody-drug conjugates. “HER2CLIMB-02 is unlikely to change the current algorithm, but it reinforces the role of tucatinib in the treatment of HER2+ metastatic breast cancer. The data further support studies in the early disease setting aiming to prevent the development of brain metastases,” said Dr. Guarneri.

The study was funded by Seagen. Dr. Hurvitz has received research funding from Ambrx, Arvinas, AstraZeneca, Bayer, Celcuity, CytomX Therapeutics, Daiichi Sankyo, Dantari Inc., Dignitana, Genentech, (Roche), G1 Therapeutics, Gilead Sciences Inc., Greenwich LifeSciences Inc., GSK, Immunomedics, Eli Lilly and Company, Loxo Oncology, MacroGenics, Novartis, OBI Pharma Inc., Orinove Inc., Orum Therapeutics, Pfizer, Phoenix Molecular Designs, Pieris Pharmaceuticals Inc., Puma Biotechnology, Radius Health, Sanofi, Seagen, and Zymeworks; has received royalties from McGraw Hill, Sage Publications, Wiley, and Wolters Kluwer; has served on the data and safety monitoring board for Alliance Foundation Trials LLC, Atossa Therapeutics, and the Quantum Leap Healthcare Collaborative; and has received honoraria from the Vaniam Group and OncLive. Her husband holds stock in ROMTech. Dr. Guarneri has been a member of the advisory boards for AstraZeneca, Daiichi Sankyo, Eisai, Eli Lilly, Exact Sciences, Gilead, Merck Serono, MSD, Novartis, Pfizer, Olema Oncology, and Pierre Fabre. She has been an invited speaker for AstraZeneca, Daiichi Sankyo, Eli Lilly, Exact Sciences, Gilead, GSK Novartis, and Zentiva.

PHOENIX – New treatments for myasthenia gravis are bringing new promise to patients, but their use must be balanced against short-term and long-term risks, according to Pushpa Narayanaswami, MD, who discussed the topic at the 2023 annual meeting of the American Association for Neuromuscular & Electrodiagnostic Medicine (AANEM).

The first Food and Drug Administration–approved drug was pyridostigmine in 1955, and it was more than 60 years before the second drug, eculizumab, gained FDA approval in 2017. Activity in more recent years has been much more brisk with the approvals of efgartigimod in 2021; ravulizumab in 2022; and efgartigimod SQ, rozanolixizumab, and zilucoplan (Japan) in 2023. Eculizumab, efgartigimod, efgartigimod SQ, ravulizumab, and rozanolixizumab are approved for patients who are anti–acetylcholine receptor (AchR) positive. Rozanolixizumab is also approved for patients who are anti–muscle-specific tyrosine kinase (MuSK) antibody positive.

The new drugs have novel mechanisms of action, giving physicians more tools to treat the condition. The mechanisms fall into two general groups: C5-complement inhibitors and neonatal Fc receptor (FcRn) agonists. Dr. Narayanaswami sought to provide guidance in thinking about how to prescribe the new drugs. “How do we really use these drugs? It’s sort of confusing in terms of where they fit in in the algorithm. I don’t pretend to have the answers, but I’m going to sort of give you a general overview of how I look at these based on the trial data and based on what we’ve done in the past,” she said during her talk.
 

Assessing the risk/benefit ratio

Myasthenia gravis treatment strategies should take into account both disease control and minimization of the adverse effects of treatment, which can include both short- and long-term concerns such as hematologic issues, changes in mood and sleep, diarrhea, infection risk, detriments to bone health, hypertension, diabetes mellitus, glaucoma, and cancer.

Disease control can be subjective. “Each patient may have a different approach to what their disease control means, so we don’t quite understand what the definition of disease control is,” said Dr. Narayanaswami. For example, “[a physician] may think of a sleep disturbance as mild, but [the patient] may not. They may not be able to function, so a lot of conversations [are needed] there,” she added.

The international consensus guidance for myasthenia gravis, first published in 2016 and updated a few years later, which Dr. Narayanaswami coauthored, suggested that minimal manifestation of disease is achievable and is relevant to patients. “These are patients who are doing well, they come to your office and say, ‘I’m doing well, I really don’t have any problem [though they may have some weakness],’ ” said Dr. Narayanaswami. In such patients, mild, grade 1 side effects from medications are acceptable.

Dr. Narayanaswami discussed the efficacy of older drugs, including evidence from a 2022 study of 367 patients, that found that 72% of patients achieved MGFA-PIS (postintervention status) of minimal manifestations within 2 years of treatment. That rose to 76% within 3 years and 84% within 5 years. “The incremental benefit [after the first 2] years was not huge, and I think that’s something to pay attention to,” said Dr. Narayanaswami. The study also found that disease duration at first visit was shorter among patients who achieved minimal manifestation at 12 months versus at 16 months. That finding follows a trend in current thinking about treatment of myasthenia gravis. “Chip (James) Howard [of Duke University], who’s my sort of guru, says you’ve got to address this like MS. You’ve got to hit them early and hit them hard. And I think we’re seeing more and more of this. If you think about it even in your clinical practice, patients who did well tended to do well early on,” said Dr. Narayanaswami. She noted an important limitation in that the study did not adjust for confounders or covariates.

In addition, the PROMISE-MG study, which Dr. Narayanaswami coauthored, found that 57%-89% of patients treated with azathioprine or mycophenolate achieved clinically meaningful improvement in a variety of different outcome measures. “More than half to two-thirds of patients do well in clinical practice with the older drugs,” said Dr. Narayanaswami. In terms of time to outcomes, the study found that it took 2-6 months of azathioprine treatment and 2-3 months of mycophenolate mofetil (MMF) treatment for 25% of patients to experience clinically meaningful improvements. It took 14-22 months and 13-18 months, respectively, for 75% of patients to achieve this benchmark.

Regarding when to consider switching to newer therapies, Dr. Narayanaswami pointed out that there is no FDA requirement that patients fail previous therapies, but insurance companies often require it before reimbursement.

Dr. Narayanaswami said that the benefits of these drugs are well known, so she focused instead on their safety profiles in clinical practice. C-5 complement inhibitors carry a risk of meningococcal infection, which has been addressed in various postmarketing studies. “I will say that data is difficult to interpret for various reasons … but the point is that there is a risk for meningococcal infections. The risk appears to be low, but it’s not zero, even if you immunize patients, and I think that’s the conversation we need to have [with patients],” she said. Other issues with C5-complement inhibitors can include headache, nasopharyngitis, diarrhea, abdominal pain, back pain, nausea, and other infections.

FcRn antagonists have a range of potential side effects, but Dr. Narayanaswami emphasized timing of vaccinations, since the drugs antagonize recycling of IgG. She said vaccines should be given before the first dose of the cycle. There are no data on their use in pregnancy, but the agents could potentially reduce the passive transfer of IgG antibodies to the fetus.
 

Treatment strategies

In clinical practice, Dr. Narayanaswami employs the newer drugs in patients who have failed older drugs, or who experience intolerable side effects. An important consideration is how long to wait before determining a failure on previous therapies. Her current inclination is to treat earlier, which leads her to consider newer drugs at 2 years after disease onset, or after 1 year if the patient has had no improvement at all. She would consider the therapies as first-line therapies in patients for whom she doesn’t feel comfortable prescribing older medications, often older or more frail patients, or patients at any age when comorbidities might contraindicate glucocorticoids.

During the Q&A session after the talk, an attendee asked Dr. Narayanaswami what she does when payers balk at paying for new drugs. She noted that payers don’t necessarily have a specific number of months in mind for patients who are quite sick. “They just want somebody to try something. That has been my experience,” she said. She also goes peer-to-peer when disputing coverage. “Sometimes you can convince them on a peer-to-peer [basis] because they don’t really know myasthenia gravis.”

Another questioner wondered if clinical trials have been done or are in progress to demonstrate that earlier treatment can lead to better results. Dr. Narayanaswami responded that several observational trials are looking at the question. “It’s challenging because sometimes we don’t know the time from diagnosis. We know the first time they came in, which is not necessarily the same as the time from diagnosis, and sometimes that can be hard to get. And, again, it’s observational data, which can be dirty,” she said.

Dr. Narayanaswami disclosed ties with Alexion, Argenx, Dianthus, GSK, Janssen, Patient Centered Outcomes Research Institute, Sanofi, and UCB.

PHOENIX – New treatments for myasthenia gravis are bringing new promise to patients, but their use must be balanced against short-term and long-term risks, according to Pushpa Narayanaswami, MD, who discussed the topic at the 2023 annual meeting of the American Association for Neuromuscular & Electrodiagnostic Medicine (AANEM).

The first Food and Drug Administration–approved drug was pyridostigmine in 1955, and it was more than 60 years before the second drug, eculizumab, gained FDA approval in 2017. Activity in more recent years has been much more brisk with the approvals of efgartigimod in 2021; ravulizumab in 2022; and efgartigimod SQ, rozanolixizumab, and zilucoplan (Japan) in 2023. Eculizumab, efgartigimod, efgartigimod SQ, ravulizumab, and rozanolixizumab are approved for patients who are anti–acetylcholine receptor (AchR) positive. Rozanolixizumab is also approved for patients who are anti–muscle-specific tyrosine kinase (MuSK) antibody positive.

The new drugs have novel mechanisms of action, giving physicians more tools to treat the condition. The mechanisms fall into two general groups: C5-complement inhibitors and neonatal Fc receptor (FcRn) agonists. Dr. Narayanaswami sought to provide guidance in thinking about how to prescribe the new drugs. “How do we really use these drugs? It’s sort of confusing in terms of where they fit in in the algorithm. I don’t pretend to have the answers, but I’m going to sort of give you a general overview of how I look at these based on the trial data and based on what we’ve done in the past,” she said during her talk.
 

Assessing the risk/benefit ratio

Myasthenia gravis treatment strategies should take into account both disease control and minimization of the adverse effects of treatment, which can include both short- and long-term concerns such as hematologic issues, changes in mood and sleep, diarrhea, infection risk, detriments to bone health, hypertension, diabetes mellitus, glaucoma, and cancer.

Disease control can be subjective. “Each patient may have a different approach to what their disease control means, so we don’t quite understand what the definition of disease control is,” said Dr. Narayanaswami. For example, “[a physician] may think of a sleep disturbance as mild, but [the patient] may not. They may not be able to function, so a lot of conversations [are needed] there,” she added.

The international consensus guidance for myasthenia gravis, first published in 2016 and updated a few years later, which Dr. Narayanaswami coauthored, suggested that minimal manifestation of disease is achievable and is relevant to patients. “These are patients who are doing well, they come to your office and say, ‘I’m doing well, I really don’t have any problem [though they may have some weakness],’ ” said Dr. Narayanaswami. In such patients, mild, grade 1 side effects from medications are acceptable.

Dr. Narayanaswami discussed the efficacy of older drugs, including evidence from a 2022 study of 367 patients, that found that 72% of patients achieved MGFA-PIS (postintervention status) of minimal manifestations within 2 years of treatment. That rose to 76% within 3 years and 84% within 5 years. “The incremental benefit [after the first 2] years was not huge, and I think that’s something to pay attention to,” said Dr. Narayanaswami. The study also found that disease duration at first visit was shorter among patients who achieved minimal manifestation at 12 months versus at 16 months. That finding follows a trend in current thinking about treatment of myasthenia gravis. “Chip (James) Howard [of Duke University], who’s my sort of guru, says you’ve got to address this like MS. You’ve got to hit them early and hit them hard. And I think we’re seeing more and more of this. If you think about it even in your clinical practice, patients who did well tended to do well early on,” said Dr. Narayanaswami. She noted an important limitation in that the study did not adjust for confounders or covariates.

In addition, the PROMISE-MG study, which Dr. Narayanaswami coauthored, found that 57%-89% of patients treated with azathioprine or mycophenolate achieved clinically meaningful improvement in a variety of different outcome measures. “More than half to two-thirds of patients do well in clinical practice with the older drugs,” said Dr. Narayanaswami. In terms of time to outcomes, the study found that it took 2-6 months of azathioprine treatment and 2-3 months of mycophenolate mofetil (MMF) treatment for 25% of patients to experience clinically meaningful improvements. It took 14-22 months and 13-18 months, respectively, for 75% of patients to achieve this benchmark.

Regarding when to consider switching to newer therapies, Dr. Narayanaswami pointed out that there is no FDA requirement that patients fail previous therapies, but insurance companies often require it before reimbursement.

Dr. Narayanaswami said that the benefits of these drugs are well known, so she focused instead on their safety profiles in clinical practice. C-5 complement inhibitors carry a risk of meningococcal infection, which has been addressed in various postmarketing studies. “I will say that data is difficult to interpret for various reasons … but the point is that there is a risk for meningococcal infections. The risk appears to be low, but it’s not zero, even if you immunize patients, and I think that’s the conversation we need to have [with patients],” she said. Other issues with C5-complement inhibitors can include headache, nasopharyngitis, diarrhea, abdominal pain, back pain, nausea, and other infections.

FcRn antagonists have a range of potential side effects, but Dr. Narayanaswami emphasized timing of vaccinations, since the drugs antagonize recycling of IgG. She said vaccines should be given before the first dose of the cycle. There are no data on their use in pregnancy, but the agents could potentially reduce the passive transfer of IgG antibodies to the fetus.
 

Treatment strategies

In clinical practice, Dr. Narayanaswami employs the newer drugs in patients who have failed older drugs, or who experience intolerable side effects. An important consideration is how long to wait before determining a failure on previous therapies. Her current inclination is to treat earlier, which leads her to consider newer drugs at 2 years after disease onset, or after 1 year if the patient has had no improvement at all. She would consider the therapies as first-line therapies in patients for whom she doesn’t feel comfortable prescribing older medications, often older or more frail patients, or patients at any age when comorbidities might contraindicate glucocorticoids.

During the Q&A session after the talk, an attendee asked Dr. Narayanaswami what she does when payers balk at paying for new drugs. She noted that payers don’t necessarily have a specific number of months in mind for patients who are quite sick. “They just want somebody to try something. That has been my experience,” she said. She also goes peer-to-peer when disputing coverage. “Sometimes you can convince them on a peer-to-peer [basis] because they don’t really know myasthenia gravis.”

Another questioner wondered if clinical trials have been done or are in progress to demonstrate that earlier treatment can lead to better results. Dr. Narayanaswami responded that several observational trials are looking at the question. “It’s challenging because sometimes we don’t know the time from diagnosis. We know the first time they came in, which is not necessarily the same as the time from diagnosis, and sometimes that can be hard to get. And, again, it’s observational data, which can be dirty,” she said.

Dr. Narayanaswami disclosed ties with Alexion, Argenx, Dianthus, GSK, Janssen, Patient Centered Outcomes Research Institute, Sanofi, and UCB.

PHOENIX – New treatments for myasthenia gravis are bringing new promise to patients, but their use must be balanced against short-term and long-term risks, according to Pushpa Narayanaswami, MD, who discussed the topic at the 2023 annual meeting of the American Association for Neuromuscular & Electrodiagnostic Medicine (AANEM).

The first Food and Drug Administration–approved drug was pyridostigmine in 1955, and it was more than 60 years before the second drug, eculizumab, gained FDA approval in 2017. Activity in more recent years has been much more brisk with the approvals of efgartigimod in 2021; ravulizumab in 2022; and efgartigimod SQ, rozanolixizumab, and zilucoplan (Japan) in 2023. Eculizumab, efgartigimod, efgartigimod SQ, ravulizumab, and rozanolixizumab are approved for patients who are anti–acetylcholine receptor (AchR) positive. Rozanolixizumab is also approved for patients who are anti–muscle-specific tyrosine kinase (MuSK) antibody positive.

The new drugs have novel mechanisms of action, giving physicians more tools to treat the condition. The mechanisms fall into two general groups: C5-complement inhibitors and neonatal Fc receptor (FcRn) agonists. Dr. Narayanaswami sought to provide guidance in thinking about how to prescribe the new drugs. “How do we really use these drugs? It’s sort of confusing in terms of where they fit in in the algorithm. I don’t pretend to have the answers, but I’m going to sort of give you a general overview of how I look at these based on the trial data and based on what we’ve done in the past,” she said during her talk.
 

Assessing the risk/benefit ratio

Myasthenia gravis treatment strategies should take into account both disease control and minimization of the adverse effects of treatment, which can include both short- and long-term concerns such as hematologic issues, changes in mood and sleep, diarrhea, infection risk, detriments to bone health, hypertension, diabetes mellitus, glaucoma, and cancer.

Disease control can be subjective. “Each patient may have a different approach to what their disease control means, so we don’t quite understand what the definition of disease control is,” said Dr. Narayanaswami. For example, “[a physician] may think of a sleep disturbance as mild, but [the patient] may not. They may not be able to function, so a lot of conversations [are needed] there,” she added.

The international consensus guidance for myasthenia gravis, first published in 2016 and updated a few years later, which Dr. Narayanaswami coauthored, suggested that minimal manifestation of disease is achievable and is relevant to patients. “These are patients who are doing well, they come to your office and say, ‘I’m doing well, I really don’t have any problem [though they may have some weakness],’ ” said Dr. Narayanaswami. In such patients, mild, grade 1 side effects from medications are acceptable.

Dr. Narayanaswami discussed the efficacy of older drugs, including evidence from a 2022 study of 367 patients, that found that 72% of patients achieved MGFA-PIS (postintervention status) of minimal manifestations within 2 years of treatment. That rose to 76% within 3 years and 84% within 5 years. “The incremental benefit [after the first 2] years was not huge, and I think that’s something to pay attention to,” said Dr. Narayanaswami. The study also found that disease duration at first visit was shorter among patients who achieved minimal manifestation at 12 months versus at 16 months. That finding follows a trend in current thinking about treatment of myasthenia gravis. “Chip (James) Howard [of Duke University], who’s my sort of guru, says you’ve got to address this like MS. You’ve got to hit them early and hit them hard. And I think we’re seeing more and more of this. If you think about it even in your clinical practice, patients who did well tended to do well early on,” said Dr. Narayanaswami. She noted an important limitation in that the study did not adjust for confounders or covariates.

In addition, the PROMISE-MG study, which Dr. Narayanaswami coauthored, found that 57%-89% of patients treated with azathioprine or mycophenolate achieved clinically meaningful improvement in a variety of different outcome measures. “More than half to two-thirds of patients do well in clinical practice with the older drugs,” said Dr. Narayanaswami. In terms of time to outcomes, the study found that it took 2-6 months of azathioprine treatment and 2-3 months of mycophenolate mofetil (MMF) treatment for 25% of patients to experience clinically meaningful improvements. It took 14-22 months and 13-18 months, respectively, for 75% of patients to achieve this benchmark.

Regarding when to consider switching to newer therapies, Dr. Narayanaswami pointed out that there is no FDA requirement that patients fail previous therapies, but insurance companies often require it before reimbursement.

Dr. Narayanaswami said that the benefits of these drugs are well known, so she focused instead on their safety profiles in clinical practice. C-5 complement inhibitors carry a risk of meningococcal infection, which has been addressed in various postmarketing studies. “I will say that data is difficult to interpret for various reasons … but the point is that there is a risk for meningococcal infections. The risk appears to be low, but it’s not zero, even if you immunize patients, and I think that’s the conversation we need to have [with patients],” she said. Other issues with C5-complement inhibitors can include headache, nasopharyngitis, diarrhea, abdominal pain, back pain, nausea, and other infections.

FcRn antagonists have a range of potential side effects, but Dr. Narayanaswami emphasized timing of vaccinations, since the drugs antagonize recycling of IgG. She said vaccines should be given before the first dose of the cycle. There are no data on their use in pregnancy, but the agents could potentially reduce the passive transfer of IgG antibodies to the fetus.
 

Treatment strategies

In clinical practice, Dr. Narayanaswami employs the newer drugs in patients who have failed older drugs, or who experience intolerable side effects. An important consideration is how long to wait before determining a failure on previous therapies. Her current inclination is to treat earlier, which leads her to consider newer drugs at 2 years after disease onset, or after 1 year if the patient has had no improvement at all. She would consider the therapies as first-line therapies in patients for whom she doesn’t feel comfortable prescribing older medications, often older or more frail patients, or patients at any age when comorbidities might contraindicate glucocorticoids.

During the Q&A session after the talk, an attendee asked Dr. Narayanaswami what she does when payers balk at paying for new drugs. She noted that payers don’t necessarily have a specific number of months in mind for patients who are quite sick. “They just want somebody to try something. That has been my experience,” she said. She also goes peer-to-peer when disputing coverage. “Sometimes you can convince them on a peer-to-peer [basis] because they don’t really know myasthenia gravis.”

Another questioner wondered if clinical trials have been done or are in progress to demonstrate that earlier treatment can lead to better results. Dr. Narayanaswami responded that several observational trials are looking at the question. “It’s challenging because sometimes we don’t know the time from diagnosis. We know the first time they came in, which is not necessarily the same as the time from diagnosis, and sometimes that can be hard to get. And, again, it’s observational data, which can be dirty,” she said.

Dr. Narayanaswami disclosed ties with Alexion, Argenx, Dianthus, GSK, Janssen, Patient Centered Outcomes Research Institute, Sanofi, and UCB.

PHOENIX – Artificial intelligence (AI) is poised to dramatically alter health care, and it presents opportunities for increased production and automation of some tasks. However, it is prone to error and ‘hallucinations’ despite an authoritative tone, so its conclusions must be verified.

Those were some of the messages from a talk by John Morren, MD, an associate professor of neurology at Case Western Reserve University, Cleveland, who spoke about AI at the 2023 annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine (AANEM).

He encouraged attendees to get involved in the conversation of AI, because it is here to stay and will have a big impact on health care. “If we’re not around the table making decisions, decisions will be made for us in our absence and won’t be in our favor,” said Dr. Morren.

He started out his talk by asking if anyone in the room had used AI. After about half raised their hands, he countered that nearly everyone likely had. Voice assistants like SIRI and Alexa, social media with curated feeds, online shopping tools that provide product suggestions, and content recommendations from streaming services like Netflix all rely on AI technology.

Within medicine, AI is already playing a role in various fields, including medical imaging, disease diagnosis, drug discovery and development, predictive analytics, personalized medicine, telemedicine, and health care management.

It also has potential to be used on the job. For example, ChatGPT can generate and refine conversations towards a specific length, format, style, and level of detail. Alternatives include Bing AI from Microsoft, Bard AI from Google, Writesonic, Copy.ai, SpinBot, HIX.AI, and Chatsonic.

Specific to medicine, Consensus is a search engine that uses AI to search for, summarize, and synthesize studies from peer-reviewed literature.
 

Trust, but verify

Dr. Morren presented some specific use cases, including patient education and responses to patient inquiries, as well as generating letters to insurance companies appealing denial of coverage claims. He also showed an example where he asked Bing AI to explain to a patient, at a sixth- to seventh-grade reading level, the red-flag symptoms of myasthenic crisis.

AI can generate summaries of clinical evidence of previous studies. Asked by this reporter how to trust the accuracies of the summaries if the user hasn’t thoroughly read the papers, he acknowledged the imperfection of AI. “I would say that if you’re going to make a decision that you would not have made normally based on the summary that it’s giving, if you can find the fact that you’re anchoring the decision on, go into the article yourself and make sure that it’s well vetted. The AI is just good to tap you on your shoulder and say, ‘hey, just consider this.’ That’s all it is. You should always trust, but verify. If the AI is forcing you to say something new that you would not say, maybe don’t do it – or at least research it to know that it’s the truth and then you elevate yourself and get yourself to the next level.”
 

Limitations

The need to verify can create its own burden, according to one attendee. “I often find I end up spending more time verifying [what ChatGPT has provided]. This seems to take more time than a traditional way of going to PubMed or UpToDate or any of the other human generated consensus way,” he said.

Dr. Morren replied that he wouldn’t recommend using ChatGPT to query medical literature. Instead he recommended Consensus, which only searches the peer-reviewed medical literature.

Another key limitation is that most AI programs are date limited: For example, ChatGPT doesn’t include information after September 2021, though this may change with paid subscriptions. He also starkly warned the audience to never enter sensitive information, including patient identifiers.

There are legal and ethical considerations to AI. Dr. Morren warned against overreliance on AI, as this could undermine compassion and lead to erosion of trust, which makes it important to disclose any use of AI-generated content.

Another attendee raised concerns that AI may be generating research content, including slides for presentations, abstracts, titles, or article text. Dr. Morren said that some organizations, such as the International Committee of Medical Journal Editors, have incorporated AI in their recommendations, stating that authors should disclose any contributions of AI to their publications. However, there is little that can be done to identify AI-generated content, leaving it up to the honor code.

Asked to make predictions about how AI will evolve in the clinic over the next 2-3 years, Dr. Morren suggested that it will likely be embedded in electronic medical records. He anticipated that it will save physicians time so that they can spend more time interacting directly with patients. He quoted Eric Topol, MD, professor of medicine at Scripps Research Translational Institute, La Jolla, Calif., as saying that AI could save 20% of a physician’s time, which could be spent with patients. Dr. Morren saw it differently. “I know where that 20% of time liberated is going to go. I’m going to see 20% more patients. I’m a realist,” he said, to audience laughter.

He also predicted that AI will be found in wearables and devices, allowing health care to expand into the patient’s home in real time. “A lot of what we’re wearing is going to be an extension of the doctor’s office,” he said.

For those hoping for more guidance, Dr. Morren noted that he is the chairman of the professional practice committee of AANEM, and the group will be putting out a position statement within the next couple of months. “It will be a little bit of a blueprint for the path going forward. There are specific things that need to be done. In research, for example, you have to ensure that datasets are diverse enough. To do that we need to have inter-institutional collaboration. We have to ensure patient privacy. Consent for this needs to be a little more explicit because this is a novel area. Those are things that need to be stipulated and ratified through a task force.”

Dr. Morren has no relevant financial disclosures.

PHOENIX – Artificial intelligence (AI) is poised to dramatically alter health care, and it presents opportunities for increased production and automation of some tasks. However, it is prone to error and ‘hallucinations’ despite an authoritative tone, so its conclusions must be verified.

Those were some of the messages from a talk by John Morren, MD, an associate professor of neurology at Case Western Reserve University, Cleveland, who spoke about AI at the 2023 annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine (AANEM).

He encouraged attendees to get involved in the conversation of AI, because it is here to stay and will have a big impact on health care. “If we’re not around the table making decisions, decisions will be made for us in our absence and won’t be in our favor,” said Dr. Morren.

He started out his talk by asking if anyone in the room had used AI. After about half raised their hands, he countered that nearly everyone likely had. Voice assistants like SIRI and Alexa, social media with curated feeds, online shopping tools that provide product suggestions, and content recommendations from streaming services like Netflix all rely on AI technology.

Within medicine, AI is already playing a role in various fields, including medical imaging, disease diagnosis, drug discovery and development, predictive analytics, personalized medicine, telemedicine, and health care management.

It also has potential to be used on the job. For example, ChatGPT can generate and refine conversations towards a specific length, format, style, and level of detail. Alternatives include Bing AI from Microsoft, Bard AI from Google, Writesonic, Copy.ai, SpinBot, HIX.AI, and Chatsonic.

Specific to medicine, Consensus is a search engine that uses AI to search for, summarize, and synthesize studies from peer-reviewed literature.
 

Trust, but verify

Dr. Morren presented some specific use cases, including patient education and responses to patient inquiries, as well as generating letters to insurance companies appealing denial of coverage claims. He also showed an example where he asked Bing AI to explain to a patient, at a sixth- to seventh-grade reading level, the red-flag symptoms of myasthenic crisis.

AI can generate summaries of clinical evidence of previous studies. Asked by this reporter how to trust the accuracies of the summaries if the user hasn’t thoroughly read the papers, he acknowledged the imperfection of AI. “I would say that if you’re going to make a decision that you would not have made normally based on the summary that it’s giving, if you can find the fact that you’re anchoring the decision on, go into the article yourself and make sure that it’s well vetted. The AI is just good to tap you on your shoulder and say, ‘hey, just consider this.’ That’s all it is. You should always trust, but verify. If the AI is forcing you to say something new that you would not say, maybe don’t do it – or at least research it to know that it’s the truth and then you elevate yourself and get yourself to the next level.”
 

Limitations

The need to verify can create its own burden, according to one attendee. “I often find I end up spending more time verifying [what ChatGPT has provided]. This seems to take more time than a traditional way of going to PubMed or UpToDate or any of the other human generated consensus way,” he said.

Dr. Morren replied that he wouldn’t recommend using ChatGPT to query medical literature. Instead he recommended Consensus, which only searches the peer-reviewed medical literature.

Another key limitation is that most AI programs are date limited: For example, ChatGPT doesn’t include information after September 2021, though this may change with paid subscriptions. He also starkly warned the audience to never enter sensitive information, including patient identifiers.

There are legal and ethical considerations to AI. Dr. Morren warned against overreliance on AI, as this could undermine compassion and lead to erosion of trust, which makes it important to disclose any use of AI-generated content.

Another attendee raised concerns that AI may be generating research content, including slides for presentations, abstracts, titles, or article text. Dr. Morren said that some organizations, such as the International Committee of Medical Journal Editors, have incorporated AI in their recommendations, stating that authors should disclose any contributions of AI to their publications. However, there is little that can be done to identify AI-generated content, leaving it up to the honor code.

Asked to make predictions about how AI will evolve in the clinic over the next 2-3 years, Dr. Morren suggested that it will likely be embedded in electronic medical records. He anticipated that it will save physicians time so that they can spend more time interacting directly with patients. He quoted Eric Topol, MD, professor of medicine at Scripps Research Translational Institute, La Jolla, Calif., as saying that AI could save 20% of a physician’s time, which could be spent with patients. Dr. Morren saw it differently. “I know where that 20% of time liberated is going to go. I’m going to see 20% more patients. I’m a realist,” he said, to audience laughter.

He also predicted that AI will be found in wearables and devices, allowing health care to expand into the patient’s home in real time. “A lot of what we’re wearing is going to be an extension of the doctor’s office,” he said.

For those hoping for more guidance, Dr. Morren noted that he is the chairman of the professional practice committee of AANEM, and the group will be putting out a position statement within the next couple of months. “It will be a little bit of a blueprint for the path going forward. There are specific things that need to be done. In research, for example, you have to ensure that datasets are diverse enough. To do that we need to have inter-institutional collaboration. We have to ensure patient privacy. Consent for this needs to be a little more explicit because this is a novel area. Those are things that need to be stipulated and ratified through a task force.”

Dr. Morren has no relevant financial disclosures.

PHOENIX – Artificial intelligence (AI) is poised to dramatically alter health care, and it presents opportunities for increased production and automation of some tasks. However, it is prone to error and ‘hallucinations’ despite an authoritative tone, so its conclusions must be verified.

Those were some of the messages from a talk by John Morren, MD, an associate professor of neurology at Case Western Reserve University, Cleveland, who spoke about AI at the 2023 annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine (AANEM).

He encouraged attendees to get involved in the conversation of AI, because it is here to stay and will have a big impact on health care. “If we’re not around the table making decisions, decisions will be made for us in our absence and won’t be in our favor,” said Dr. Morren.

He started out his talk by asking if anyone in the room had used AI. After about half raised their hands, he countered that nearly everyone likely had. Voice assistants like SIRI and Alexa, social media with curated feeds, online shopping tools that provide product suggestions, and content recommendations from streaming services like Netflix all rely on AI technology.

Within medicine, AI is already playing a role in various fields, including medical imaging, disease diagnosis, drug discovery and development, predictive analytics, personalized medicine, telemedicine, and health care management.

It also has potential to be used on the job. For example, ChatGPT can generate and refine conversations towards a specific length, format, style, and level of detail. Alternatives include Bing AI from Microsoft, Bard AI from Google, Writesonic, Copy.ai, SpinBot, HIX.AI, and Chatsonic.

Specific to medicine, Consensus is a search engine that uses AI to search for, summarize, and synthesize studies from peer-reviewed literature.
 

Trust, but verify

Dr. Morren presented some specific use cases, including patient education and responses to patient inquiries, as well as generating letters to insurance companies appealing denial of coverage claims. He also showed an example where he asked Bing AI to explain to a patient, at a sixth- to seventh-grade reading level, the red-flag symptoms of myasthenic crisis.

AI can generate summaries of clinical evidence of previous studies. Asked by this reporter how to trust the accuracies of the summaries if the user hasn’t thoroughly read the papers, he acknowledged the imperfection of AI. “I would say that if you’re going to make a decision that you would not have made normally based on the summary that it’s giving, if you can find the fact that you’re anchoring the decision on, go into the article yourself and make sure that it’s well vetted. The AI is just good to tap you on your shoulder and say, ‘hey, just consider this.’ That’s all it is. You should always trust, but verify. If the AI is forcing you to say something new that you would not say, maybe don’t do it – or at least research it to know that it’s the truth and then you elevate yourself and get yourself to the next level.”
 

Limitations

The need to verify can create its own burden, according to one attendee. “I often find I end up spending more time verifying [what ChatGPT has provided]. This seems to take more time than a traditional way of going to PubMed or UpToDate or any of the other human generated consensus way,” he said.

Dr. Morren replied that he wouldn’t recommend using ChatGPT to query medical literature. Instead he recommended Consensus, which only searches the peer-reviewed medical literature.

Another key limitation is that most AI programs are date limited: For example, ChatGPT doesn’t include information after September 2021, though this may change with paid subscriptions. He also starkly warned the audience to never enter sensitive information, including patient identifiers.

There are legal and ethical considerations to AI. Dr. Morren warned against overreliance on AI, as this could undermine compassion and lead to erosion of trust, which makes it important to disclose any use of AI-generated content.

Another attendee raised concerns that AI may be generating research content, including slides for presentations, abstracts, titles, or article text. Dr. Morren said that some organizations, such as the International Committee of Medical Journal Editors, have incorporated AI in their recommendations, stating that authors should disclose any contributions of AI to their publications. However, there is little that can be done to identify AI-generated content, leaving it up to the honor code.

Asked to make predictions about how AI will evolve in the clinic over the next 2-3 years, Dr. Morren suggested that it will likely be embedded in electronic medical records. He anticipated that it will save physicians time so that they can spend more time interacting directly with patients. He quoted Eric Topol, MD, professor of medicine at Scripps Research Translational Institute, La Jolla, Calif., as saying that AI could save 20% of a physician’s time, which could be spent with patients. Dr. Morren saw it differently. “I know where that 20% of time liberated is going to go. I’m going to see 20% more patients. I’m a realist,” he said, to audience laughter.

He also predicted that AI will be found in wearables and devices, allowing health care to expand into the patient’s home in real time. “A lot of what we’re wearing is going to be an extension of the doctor’s office,” he said.

For those hoping for more guidance, Dr. Morren noted that he is the chairman of the professional practice committee of AANEM, and the group will be putting out a position statement within the next couple of months. “It will be a little bit of a blueprint for the path going forward. There are specific things that need to be done. In research, for example, you have to ensure that datasets are diverse enough. To do that we need to have inter-institutional collaboration. We have to ensure patient privacy. Consent for this needs to be a little more explicit because this is a novel area. Those are things that need to be stipulated and ratified through a task force.”

Dr. Morren has no relevant financial disclosures.

PHOENIX – The prevalence of myasthenia gravis is about 0.13% among U.S. adults, and the condition is more common in Whites than in African Americans, according to a new analysis of the National Institutes of Health All of Us database. The prevalence is higher than what has been seen in other studies, which could represent a true difference in prevalence, or reflect limitations of the database.

Worldwide estimates suggest that myasthenia gravis affects 700,000 people globally, with incidence rates ranging between 6.3 and 29 per 1,000,000 person-years in Europe and a prevalence between 111.7 and 361 per 1,000,000. Data from Australia, Taiwan, and South Korea also show evidence of increased prevalence in recent years.

However, there is little data about the prevalence of myasthenia gravis in the United States, or about differences between racial groups, according to Bhaskar Roy, MBBS, who presented the study at the 2023 annual meeting of the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM). He noted that most studies are outdated, and the most recent study focused on ocular myasthenia gravis.
 

True incidence or artifact?

The finding is surprising and may be an artifact of the immature nature of the All of Us database, according to Srikanth Muppidi, MD, who asked about the limitation during the Q&A session following the talk. “The incidence of 0.13 is definitely higher than what we would think would be the true incidence of myasthenia gravis from [clinical experience]. It’s possible that our understanding of true incidence is wrong and this is the actual incidence. What I would like them to do, and I think they’re trying to do, is to look at this finding [and compare it with] other more mature databases and other regional databases. One of the current challenges of All of Us is that our patients are basically being recruited from some parts of the country, and the middle of the country has hardly any presence in the database, so it becomes really challenging to understand it,” Dr. Muppidi said in an interview.

However, Dr. Muppidi, who is a clinical professor of neurology at Stanford (Calif.) Medicine, noted that the All of Us database is still growing. When it has recruited more patients with a diverse population, “it [will be a] valuable source for rare diseases to try to understand true incidence of those diseases,” he said.
 

Understanding the true prevalence

Dr. Roy recognized the geographic limitations of the database. “Some states, particularly Massachusetts, New York, and California, had a lot of patients in the database, where there were no patients from many states,” said Dr. Roy, associate professor of neurology at Yale University, New Haven, Conn.

He said that the group is working with other databases, including UK Biobank. “The goal is to incorporate all of these databases together [to determine the true incidence],” said Dr. Roy.

It’s critical to understand the true prevalence of myasthenia gravis since new therapies are in development and coming to market. “I worry that myasthenia gravis might be considered less common than it truly is, and that will limit growth of the field if the feeling is that there are not that many [myasthenia gravis patients] in the country,” said Dr. Muppidi.

The study included data from 369,297 adult patients, using Systematized Nomenclature of Medicine (SNOMED) and International Classification of Diseases (ICD) codes to identify patients with myasthenia gravis. There were 479 cases of myasthenia gravis, for a prevalence of 0.13 (95% confidence interval [CI], 0.12-0.14). Of myasthenia gravis patients, 65% were female and the mean age was 64 years. The prevalence of myasthenia gravis in White individuals was 0.16 (95% CI, 0.15-0.18), of which 63% were female, and the mean age was 66 years. The prevalence among Black individuals was 0.078 (95% CI, 0.060-0.10), with 77% of the population female and a mean age of 58 years. The prevalence in Hispanics was 0.091 (95% CI, 0.070-0.12), with 80% female and a mean age of 58 years. Among Asians, the prevalence was 0.056 (95% CI, 0.025-0.12) and 57% were female, with a mean age of 58 years.

The researchers also looked at the EXPLORE-MG database drawn from Yale (n = 3,269,000), which showed a much lower overall myasthenia gravis prevalence of 0.019 (95% CI, 0.017-0.020), a female proportion of 46.8%, and a mean age of 56.6 years. Notably, EXPLORE-MG had a lower proportion of women and a younger population than All of Us.

The researchers compared data from All of Us with other databases for other conditions. The prevalence of ALS was the same as in other conditions, while diabetic neuropathy was significantly lower (2.7 versus 28.5-50 among diabetic patients) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) was higher (0.084 versus 0.028).

Dr. Muppidi has been on advisory boards for Alexion, Argenx, UBC, and Immunovant. Dr. Roy has consulted for Alexion, Takeda Pharmaceuticals, and Argenx and owns stock in Cabaletta Bio. He has received research support from Takeda, Abcuro, and Argenx.

PHOENIX – The prevalence of myasthenia gravis is about 0.13% among U.S. adults, and the condition is more common in Whites than in African Americans, according to a new analysis of the National Institutes of Health All of Us database. The prevalence is higher than what has been seen in other studies, which could represent a true difference in prevalence, or reflect limitations of the database.

Worldwide estimates suggest that myasthenia gravis affects 700,000 people globally, with incidence rates ranging between 6.3 and 29 per 1,000,000 person-years in Europe and a prevalence between 111.7 and 361 per 1,000,000. Data from Australia, Taiwan, and South Korea also show evidence of increased prevalence in recent years.

However, there is little data about the prevalence of myasthenia gravis in the United States, or about differences between racial groups, according to Bhaskar Roy, MBBS, who presented the study at the 2023 annual meeting of the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM). He noted that most studies are outdated, and the most recent study focused on ocular myasthenia gravis.
 

True incidence or artifact?

The finding is surprising and may be an artifact of the immature nature of the All of Us database, according to Srikanth Muppidi, MD, who asked about the limitation during the Q&A session following the talk. “The incidence of 0.13 is definitely higher than what we would think would be the true incidence of myasthenia gravis from [clinical experience]. It’s possible that our understanding of true incidence is wrong and this is the actual incidence. What I would like them to do, and I think they’re trying to do, is to look at this finding [and compare it with] other more mature databases and other regional databases. One of the current challenges of All of Us is that our patients are basically being recruited from some parts of the country, and the middle of the country has hardly any presence in the database, so it becomes really challenging to understand it,” Dr. Muppidi said in an interview.

However, Dr. Muppidi, who is a clinical professor of neurology at Stanford (Calif.) Medicine, noted that the All of Us database is still growing. When it has recruited more patients with a diverse population, “it [will be a] valuable source for rare diseases to try to understand true incidence of those diseases,” he said.
 

Understanding the true prevalence

Dr. Roy recognized the geographic limitations of the database. “Some states, particularly Massachusetts, New York, and California, had a lot of patients in the database, where there were no patients from many states,” said Dr. Roy, associate professor of neurology at Yale University, New Haven, Conn.

He said that the group is working with other databases, including UK Biobank. “The goal is to incorporate all of these databases together [to determine the true incidence],” said Dr. Roy.

It’s critical to understand the true prevalence of myasthenia gravis since new therapies are in development and coming to market. “I worry that myasthenia gravis might be considered less common than it truly is, and that will limit growth of the field if the feeling is that there are not that many [myasthenia gravis patients] in the country,” said Dr. Muppidi.

The study included data from 369,297 adult patients, using Systematized Nomenclature of Medicine (SNOMED) and International Classification of Diseases (ICD) codes to identify patients with myasthenia gravis. There were 479 cases of myasthenia gravis, for a prevalence of 0.13 (95% confidence interval [CI], 0.12-0.14). Of myasthenia gravis patients, 65% were female and the mean age was 64 years. The prevalence of myasthenia gravis in White individuals was 0.16 (95% CI, 0.15-0.18), of which 63% were female, and the mean age was 66 years. The prevalence among Black individuals was 0.078 (95% CI, 0.060-0.10), with 77% of the population female and a mean age of 58 years. The prevalence in Hispanics was 0.091 (95% CI, 0.070-0.12), with 80% female and a mean age of 58 years. Among Asians, the prevalence was 0.056 (95% CI, 0.025-0.12) and 57% were female, with a mean age of 58 years.

The researchers also looked at the EXPLORE-MG database drawn from Yale (n = 3,269,000), which showed a much lower overall myasthenia gravis prevalence of 0.019 (95% CI, 0.017-0.020), a female proportion of 46.8%, and a mean age of 56.6 years. Notably, EXPLORE-MG had a lower proportion of women and a younger population than All of Us.

The researchers compared data from All of Us with other databases for other conditions. The prevalence of ALS was the same as in other conditions, while diabetic neuropathy was significantly lower (2.7 versus 28.5-50 among diabetic patients) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) was higher (0.084 versus 0.028).

Dr. Muppidi has been on advisory boards for Alexion, Argenx, UBC, and Immunovant. Dr. Roy has consulted for Alexion, Takeda Pharmaceuticals, and Argenx and owns stock in Cabaletta Bio. He has received research support from Takeda, Abcuro, and Argenx.

PHOENIX – The prevalence of myasthenia gravis is about 0.13% among U.S. adults, and the condition is more common in Whites than in African Americans, according to a new analysis of the National Institutes of Health All of Us database. The prevalence is higher than what has been seen in other studies, which could represent a true difference in prevalence, or reflect limitations of the database.

Worldwide estimates suggest that myasthenia gravis affects 700,000 people globally, with incidence rates ranging between 6.3 and 29 per 1,000,000 person-years in Europe and a prevalence between 111.7 and 361 per 1,000,000. Data from Australia, Taiwan, and South Korea also show evidence of increased prevalence in recent years.

However, there is little data about the prevalence of myasthenia gravis in the United States, or about differences between racial groups, according to Bhaskar Roy, MBBS, who presented the study at the 2023 annual meeting of the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM). He noted that most studies are outdated, and the most recent study focused on ocular myasthenia gravis.
 

True incidence or artifact?

The finding is surprising and may be an artifact of the immature nature of the All of Us database, according to Srikanth Muppidi, MD, who asked about the limitation during the Q&A session following the talk. “The incidence of 0.13 is definitely higher than what we would think would be the true incidence of myasthenia gravis from [clinical experience]. It’s possible that our understanding of true incidence is wrong and this is the actual incidence. What I would like them to do, and I think they’re trying to do, is to look at this finding [and compare it with] other more mature databases and other regional databases. One of the current challenges of All of Us is that our patients are basically being recruited from some parts of the country, and the middle of the country has hardly any presence in the database, so it becomes really challenging to understand it,” Dr. Muppidi said in an interview.

However, Dr. Muppidi, who is a clinical professor of neurology at Stanford (Calif.) Medicine, noted that the All of Us database is still growing. When it has recruited more patients with a diverse population, “it [will be a] valuable source for rare diseases to try to understand true incidence of those diseases,” he said.
 

Understanding the true prevalence

Dr. Roy recognized the geographic limitations of the database. “Some states, particularly Massachusetts, New York, and California, had a lot of patients in the database, where there were no patients from many states,” said Dr. Roy, associate professor of neurology at Yale University, New Haven, Conn.

He said that the group is working with other databases, including UK Biobank. “The goal is to incorporate all of these databases together [to determine the true incidence],” said Dr. Roy.

It’s critical to understand the true prevalence of myasthenia gravis since new therapies are in development and coming to market. “I worry that myasthenia gravis might be considered less common than it truly is, and that will limit growth of the field if the feeling is that there are not that many [myasthenia gravis patients] in the country,” said Dr. Muppidi.

The study included data from 369,297 adult patients, using Systematized Nomenclature of Medicine (SNOMED) and International Classification of Diseases (ICD) codes to identify patients with myasthenia gravis. There were 479 cases of myasthenia gravis, for a prevalence of 0.13 (95% confidence interval [CI], 0.12-0.14). Of myasthenia gravis patients, 65% were female and the mean age was 64 years. The prevalence of myasthenia gravis in White individuals was 0.16 (95% CI, 0.15-0.18), of which 63% were female, and the mean age was 66 years. The prevalence among Black individuals was 0.078 (95% CI, 0.060-0.10), with 77% of the population female and a mean age of 58 years. The prevalence in Hispanics was 0.091 (95% CI, 0.070-0.12), with 80% female and a mean age of 58 years. Among Asians, the prevalence was 0.056 (95% CI, 0.025-0.12) and 57% were female, with a mean age of 58 years.

The researchers also looked at the EXPLORE-MG database drawn from Yale (n = 3,269,000), which showed a much lower overall myasthenia gravis prevalence of 0.019 (95% CI, 0.017-0.020), a female proportion of 46.8%, and a mean age of 56.6 years. Notably, EXPLORE-MG had a lower proportion of women and a younger population than All of Us.

The researchers compared data from All of Us with other databases for other conditions. The prevalence of ALS was the same as in other conditions, while diabetic neuropathy was significantly lower (2.7 versus 28.5-50 among diabetic patients) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) was higher (0.084 versus 0.028).

Dr. Muppidi has been on advisory boards for Alexion, Argenx, UBC, and Immunovant. Dr. Roy has consulted for Alexion, Takeda Pharmaceuticals, and Argenx and owns stock in Cabaletta Bio. He has received research support from Takeda, Abcuro, and Argenx.

Cognitive issues in children with Duchenne muscular dystrophy (DMD) are linked to worse outcomes, but limited access to specialists and limited resources make this problem difficult to address. A new tool from the National Institutes of Health, called NIH Toolbox, could improve that outcome, according to Mathula Thangarajh, MD, PhD, who has conducted research in the field.

“When we talk to families and parents, they are able to identify that even during infancy that [children with DMD] have delayed cognitive function. This includes speech delay, but also language and adaptive skills. We also know that those children with speech delay, which is really a very commonly reported phenotype in up to 50%, go on to have school-based needs. They may repeat [grades] in elementary years, but they also use more resources at school,” said Dr. Thangarajh, who is an assistant professor of neurology at the Children’s Hospital of Richmond at Virginia Commonwealth University, Richmond, during a talk at the 2023 annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine (AANEM).

Children’s Hospital of Richmond at Virginia Commonwealth University

A previous natural history study that utilized the Pediatric Quality of Life assessment also showed that DMD patients reported the lowest scores in brain health, including emotional health and school performance.

Other research has shown a correlation between cognitive function and survival in DMD. “This suggests that health maintenance may play an important role [in outcomes],” said Dr. Thangarajh. Another study found a correlation between psychomotor delay that required school-based interventions and earlier loss of ambulation, lower cardiac ejection fraction, and worse pulmonary function. The researchers also found that boys with cognitive delay were diagnosed at an earlier age, and yet had delays in diagnosis and worse motor function, pulmonary health, and cardiac health outcomes. On average, they lost ambulatory ability 2 years earlier.

A study by Dr. Thangarajh’s group showed that patients with speech delay and lower IQ had lower performance in timed tests, including 6-minute walk test distance and scored an average of 2 points lower on the North Star Ambulatory Assessment.
 

A tool for continuous cognitive assessment

The Centers for Disease Control and Prevention–supported DMD CARE guidelines only say that neuropsychological evaluations should be considered at diagnosis, but is essential if concerns arise about developmental progress. However, the Muscular Dystrophy Association has found barriers both in access to specialists, with an average wait time of 1-2 years, and burdensome out-of-pocket costs.

Those issues prompted Dr. Thangarajh to look for an alternative solution. At the time that she embarked on this work, the NIH was interested in technologies to assess neurobehavioral issues across different diseases. The resulting NIH Toolbox iPad app was driven largely by failed clinical trials in dementia, and the aim was to be able to provide continuous assessment over time. “It will allow for assessments across the lifespan, so you can use the same construct from age 3 to 80-plus,” said Dr. Thangarajh. It can also normalize population factors, such as annual household income and mother’s IQ.

She set out to validate the NIH Toolbox in children with DMD. The toolbox includes measures of crystalized cognition and fluid cognition. The former encompasses vocabulary and reading ability, which are strongly predicted by socioeconomic status and maternal IQ. On the other hand, fluid cognition includes cognitive features that develop across the lifespan and is directly related to academic underperformance in DMD patients.

Dr. Thangarajh’s group assessed 30 boys with DMD and found that crystallized cognition was normal, but they had a deficit in fluid cognition. They found deficits within several subdomains of fluid cognition. “This tells us that the NIH Toolbox was able to replicate what we had known in the literature, that these boys really have lower intellectual capacity, but they also have significant weakness in fluid cognition,” she said.

She also wanted to examine changes over time by testing the boys at a 1-year interview. “What we found was that they are not making as much gain in fluid cognition as we would like. They are just making marginal improvements over time. This has implications on how often we should screen them, but also not be over reliant on using school-based resources for them to get tested,” said Dr. Thangarajh.

Her group’s analysis of a dataset of 55 boys provided by PTC Therapeutics revealed a difference by age in a test of working memory. “What we found was that boys who are actually greater than 9 years, compared with those who are less than 9 years, they actually had a reversal of development-based improvement. The older they get, they were not making as much gains as you would expect,” said Dr. Thangarajh.

She went on to discuss psychosocial determinants of cognitive health in DMD. It is known that women who are carriers of the dystrophin mutation can underperform in cognitively stressful tasks, leading her to wonder if this could lead to transgenerational risk to offspring with DMD. Her group tested women who were carriers of the mutation with the NIH Toolbox and found that they had lower fluid cognition than noncarriers. They then tested 65 dyads of mothers and children, and found a correlation, but only when it came to inhibitory control, which required the individual to note the direction of an arrow while ignoring surrounding arrows pointing in various directions.

Next, the researchers examined neighborhoods and their impact on cognitive health, which can be affected by the presence of green spaces, access to public transportation and good nutrition, and other factors. There were significant deficits associated with residence zip codes. “We were pretty shocked. Someone who is not in a socially vulnerable region is scoring slightly below average, but someone who is in a very socially vulnerable neighborhood is only scoring 75 [age-adjusted score] on the NIH toolbox. So with this, we can conclude that carrier women are vulnerable in certain cognitive domains, but also children who come from socially vulnerable [situations] have poor cognitive control. This, again, has implications on how often we should screen and how much we should overly rely on school-based resources for these individuals,” said Dr. Thangarajh.
 

Overcoming a significant barrier

The NIH Toolbox has a lot of potential to improve DMD care, according to Dianna Quan, MD, who is the incoming president of AANEM, and professor of neurology at the University of Colorado at Denver, Aurora. “There’s this huge problem in terms of getting people in to see neuropsychologists and having formal evaluations. I think that’s a huge barrier. If we have people able to access this toolkit, which is simple and easily and universally accessible, how wonderful is that? I think that will be a really great improvement on what’s going on right now. It allows people to easily screen for these cognitive disabilities and make sure that we address them,” Dr. Quan said in an interview.

Asked how the tool could specifically improve care, Dr. Quan suggested that the first step is to understand the contributing factors to cognitive issues, whether they are biological, social, or a combination. “Some of them we can modify, potentially, through addressing the social environment. Some of those biologic factors may also be modifiable with many of the new drug studies that are coming.”

Dr. Thangarajh has received speaker honoraria from NS Pharma and PTC Therapeutics. Dr. Quan has received funding from Alnylam, Pfizer, Cytokinetics, Momenta, and Argenx.

Cognitive issues in children with Duchenne muscular dystrophy (DMD) are linked to worse outcomes, but limited access to specialists and limited resources make this problem difficult to address. A new tool from the National Institutes of Health, called NIH Toolbox, could improve that outcome, according to Mathula Thangarajh, MD, PhD, who has conducted research in the field.

“When we talk to families and parents, they are able to identify that even during infancy that [children with DMD] have delayed cognitive function. This includes speech delay, but also language and adaptive skills. We also know that those children with speech delay, which is really a very commonly reported phenotype in up to 50%, go on to have school-based needs. They may repeat [grades] in elementary years, but they also use more resources at school,” said Dr. Thangarajh, who is an assistant professor of neurology at the Children’s Hospital of Richmond at Virginia Commonwealth University, Richmond, during a talk at the 2023 annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine (AANEM).

Children’s Hospital of Richmond at Virginia Commonwealth University

A previous natural history study that utilized the Pediatric Quality of Life assessment also showed that DMD patients reported the lowest scores in brain health, including emotional health and school performance.

Other research has shown a correlation between cognitive function and survival in DMD. “This suggests that health maintenance may play an important role [in outcomes],” said Dr. Thangarajh. Another study found a correlation between psychomotor delay that required school-based interventions and earlier loss of ambulation, lower cardiac ejection fraction, and worse pulmonary function. The researchers also found that boys with cognitive delay were diagnosed at an earlier age, and yet had delays in diagnosis and worse motor function, pulmonary health, and cardiac health outcomes. On average, they lost ambulatory ability 2 years earlier.

A study by Dr. Thangarajh’s group showed that patients with speech delay and lower IQ had lower performance in timed tests, including 6-minute walk test distance and scored an average of 2 points lower on the North Star Ambulatory Assessment.
 

A tool for continuous cognitive assessment

The Centers for Disease Control and Prevention–supported DMD CARE guidelines only say that neuropsychological evaluations should be considered at diagnosis, but is essential if concerns arise about developmental progress. However, the Muscular Dystrophy Association has found barriers both in access to specialists, with an average wait time of 1-2 years, and burdensome out-of-pocket costs.

Those issues prompted Dr. Thangarajh to look for an alternative solution. At the time that she embarked on this work, the NIH was interested in technologies to assess neurobehavioral issues across different diseases. The resulting NIH Toolbox iPad app was driven largely by failed clinical trials in dementia, and the aim was to be able to provide continuous assessment over time. “It will allow for assessments across the lifespan, so you can use the same construct from age 3 to 80-plus,” said Dr. Thangarajh. It can also normalize population factors, such as annual household income and mother’s IQ.

She set out to validate the NIH Toolbox in children with DMD. The toolbox includes measures of crystalized cognition and fluid cognition. The former encompasses vocabulary and reading ability, which are strongly predicted by socioeconomic status and maternal IQ. On the other hand, fluid cognition includes cognitive features that develop across the lifespan and is directly related to academic underperformance in DMD patients.

Dr. Thangarajh’s group assessed 30 boys with DMD and found that crystallized cognition was normal, but they had a deficit in fluid cognition. They found deficits within several subdomains of fluid cognition. “This tells us that the NIH Toolbox was able to replicate what we had known in the literature, that these boys really have lower intellectual capacity, but they also have significant weakness in fluid cognition,” she said.

She also wanted to examine changes over time by testing the boys at a 1-year interview. “What we found was that they are not making as much gain in fluid cognition as we would like. They are just making marginal improvements over time. This has implications on how often we should screen them, but also not be over reliant on using school-based resources for them to get tested,” said Dr. Thangarajh.

Her group’s analysis of a dataset of 55 boys provided by PTC Therapeutics revealed a difference by age in a test of working memory. “What we found was that boys who are actually greater than 9 years, compared with those who are less than 9 years, they actually had a reversal of development-based improvement. The older they get, they were not making as much gains as you would expect,” said Dr. Thangarajh.

She went on to discuss psychosocial determinants of cognitive health in DMD. It is known that women who are carriers of the dystrophin mutation can underperform in cognitively stressful tasks, leading her to wonder if this could lead to transgenerational risk to offspring with DMD. Her group tested women who were carriers of the mutation with the NIH Toolbox and found that they had lower fluid cognition than noncarriers. They then tested 65 dyads of mothers and children, and found a correlation, but only when it came to inhibitory control, which required the individual to note the direction of an arrow while ignoring surrounding arrows pointing in various directions.

Next, the researchers examined neighborhoods and their impact on cognitive health, which can be affected by the presence of green spaces, access to public transportation and good nutrition, and other factors. There were significant deficits associated with residence zip codes. “We were pretty shocked. Someone who is not in a socially vulnerable region is scoring slightly below average, but someone who is in a very socially vulnerable neighborhood is only scoring 75 [age-adjusted score] on the NIH toolbox. So with this, we can conclude that carrier women are vulnerable in certain cognitive domains, but also children who come from socially vulnerable [situations] have poor cognitive control. This, again, has implications on how often we should screen and how much we should overly rely on school-based resources for these individuals,” said Dr. Thangarajh.
 

Overcoming a significant barrier

The NIH Toolbox has a lot of potential to improve DMD care, according to Dianna Quan, MD, who is the incoming president of AANEM, and professor of neurology at the University of Colorado at Denver, Aurora. “There’s this huge problem in terms of getting people in to see neuropsychologists and having formal evaluations. I think that’s a huge barrier. If we have people able to access this toolkit, which is simple and easily and universally accessible, how wonderful is that? I think that will be a really great improvement on what’s going on right now. It allows people to easily screen for these cognitive disabilities and make sure that we address them,” Dr. Quan said in an interview.

Asked how the tool could specifically improve care, Dr. Quan suggested that the first step is to understand the contributing factors to cognitive issues, whether they are biological, social, or a combination. “Some of them we can modify, potentially, through addressing the social environment. Some of those biologic factors may also be modifiable with many of the new drug studies that are coming.”

Dr. Thangarajh has received speaker honoraria from NS Pharma and PTC Therapeutics. Dr. Quan has received funding from Alnylam, Pfizer, Cytokinetics, Momenta, and Argenx.

Cognitive issues in children with Duchenne muscular dystrophy (DMD) are linked to worse outcomes, but limited access to specialists and limited resources make this problem difficult to address. A new tool from the National Institutes of Health, called NIH Toolbox, could improve that outcome, according to Mathula Thangarajh, MD, PhD, who has conducted research in the field.

“When we talk to families and parents, they are able to identify that even during infancy that [children with DMD] have delayed cognitive function. This includes speech delay, but also language and adaptive skills. We also know that those children with speech delay, which is really a very commonly reported phenotype in up to 50%, go on to have school-based needs. They may repeat [grades] in elementary years, but they also use more resources at school,” said Dr. Thangarajh, who is an assistant professor of neurology at the Children’s Hospital of Richmond at Virginia Commonwealth University, Richmond, during a talk at the 2023 annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine (AANEM).

Children’s Hospital of Richmond at Virginia Commonwealth University

A previous natural history study that utilized the Pediatric Quality of Life assessment also showed that DMD patients reported the lowest scores in brain health, including emotional health and school performance.

Other research has shown a correlation between cognitive function and survival in DMD. “This suggests that health maintenance may play an important role [in outcomes],” said Dr. Thangarajh. Another study found a correlation between psychomotor delay that required school-based interventions and earlier loss of ambulation, lower cardiac ejection fraction, and worse pulmonary function. The researchers also found that boys with cognitive delay were diagnosed at an earlier age, and yet had delays in diagnosis and worse motor function, pulmonary health, and cardiac health outcomes. On average, they lost ambulatory ability 2 years earlier.

A study by Dr. Thangarajh’s group showed that patients with speech delay and lower IQ had lower performance in timed tests, including 6-minute walk test distance and scored an average of 2 points lower on the North Star Ambulatory Assessment.
 

A tool for continuous cognitive assessment

The Centers for Disease Control and Prevention–supported DMD CARE guidelines only say that neuropsychological evaluations should be considered at diagnosis, but is essential if concerns arise about developmental progress. However, the Muscular Dystrophy Association has found barriers both in access to specialists, with an average wait time of 1-2 years, and burdensome out-of-pocket costs.

Those issues prompted Dr. Thangarajh to look for an alternative solution. At the time that she embarked on this work, the NIH was interested in technologies to assess neurobehavioral issues across different diseases. The resulting NIH Toolbox iPad app was driven largely by failed clinical trials in dementia, and the aim was to be able to provide continuous assessment over time. “It will allow for assessments across the lifespan, so you can use the same construct from age 3 to 80-plus,” said Dr. Thangarajh. It can also normalize population factors, such as annual household income and mother’s IQ.

She set out to validate the NIH Toolbox in children with DMD. The toolbox includes measures of crystalized cognition and fluid cognition. The former encompasses vocabulary and reading ability, which are strongly predicted by socioeconomic status and maternal IQ. On the other hand, fluid cognition includes cognitive features that develop across the lifespan and is directly related to academic underperformance in DMD patients.

Dr. Thangarajh’s group assessed 30 boys with DMD and found that crystallized cognition was normal, but they had a deficit in fluid cognition. They found deficits within several subdomains of fluid cognition. “This tells us that the NIH Toolbox was able to replicate what we had known in the literature, that these boys really have lower intellectual capacity, but they also have significant weakness in fluid cognition,” she said.

She also wanted to examine changes over time by testing the boys at a 1-year interview. “What we found was that they are not making as much gain in fluid cognition as we would like. They are just making marginal improvements over time. This has implications on how often we should screen them, but also not be over reliant on using school-based resources for them to get tested,” said Dr. Thangarajh.

Her group’s analysis of a dataset of 55 boys provided by PTC Therapeutics revealed a difference by age in a test of working memory. “What we found was that boys who are actually greater than 9 years, compared with those who are less than 9 years, they actually had a reversal of development-based improvement. The older they get, they were not making as much gains as you would expect,” said Dr. Thangarajh.

She went on to discuss psychosocial determinants of cognitive health in DMD. It is known that women who are carriers of the dystrophin mutation can underperform in cognitively stressful tasks, leading her to wonder if this could lead to transgenerational risk to offspring with DMD. Her group tested women who were carriers of the mutation with the NIH Toolbox and found that they had lower fluid cognition than noncarriers. They then tested 65 dyads of mothers and children, and found a correlation, but only when it came to inhibitory control, which required the individual to note the direction of an arrow while ignoring surrounding arrows pointing in various directions.

Next, the researchers examined neighborhoods and their impact on cognitive health, which can be affected by the presence of green spaces, access to public transportation and good nutrition, and other factors. There were significant deficits associated with residence zip codes. “We were pretty shocked. Someone who is not in a socially vulnerable region is scoring slightly below average, but someone who is in a very socially vulnerable neighborhood is only scoring 75 [age-adjusted score] on the NIH toolbox. So with this, we can conclude that carrier women are vulnerable in certain cognitive domains, but also children who come from socially vulnerable [situations] have poor cognitive control. This, again, has implications on how often we should screen and how much we should overly rely on school-based resources for these individuals,” said Dr. Thangarajh.
 

Overcoming a significant barrier

The NIH Toolbox has a lot of potential to improve DMD care, according to Dianna Quan, MD, who is the incoming president of AANEM, and professor of neurology at the University of Colorado at Denver, Aurora. “There’s this huge problem in terms of getting people in to see neuropsychologists and having formal evaluations. I think that’s a huge barrier. If we have people able to access this toolkit, which is simple and easily and universally accessible, how wonderful is that? I think that will be a really great improvement on what’s going on right now. It allows people to easily screen for these cognitive disabilities and make sure that we address them,” Dr. Quan said in an interview.

Asked how the tool could specifically improve care, Dr. Quan suggested that the first step is to understand the contributing factors to cognitive issues, whether they are biological, social, or a combination. “Some of them we can modify, potentially, through addressing the social environment. Some of those biologic factors may also be modifiable with many of the new drug studies that are coming.”

Dr. Thangarajh has received speaker honoraria from NS Pharma and PTC Therapeutics. Dr. Quan has received funding from Alnylam, Pfizer, Cytokinetics, Momenta, and Argenx.

PHOENIX – New therapies are on the horizon for genetic neuromuscular diseases, and this will raise both hopes for patients and challenges for neurologists. Following successful genetic treatments for ALS, hereditary amyloidosis, and spinal muscular atrophy, therapies for conditions like Charcot-Marie-Tooth (CMT) neuropathy are set to change neurology practice, according to Nicolas Madigan, MBBCh, PhD, who spoke at the 2023 annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine (AANEM).

“I think we will very soon be in a position to tell these patients that they might actually have a better treatment outcome with a genetic treatment than if they had a sporadic or inflammatory disorder,” said Dr. Madigan, who is an assistant professor of clinical research at Mayo Clinic, Rochester, N.Y.

To illustrate how genetic therapies are changing neurology practice, Dr. Madigan focused his talk on CMT neuropathy, which is the most common hereditary neuropathy and, as a result, has become a prime focus of gene therapy development. “In a city of about a million people, there will be 100-800 patients with one of these disorders,” said Dr. Madigan.
 

Case report illustrates a change in approach

There are more than 100 known genes that can contribute to CMT, but about 90% of patients harbor alterations in one of four genes: PMP22, GJB1, MFN2, and MPZ.

The trick is determining which patients are candidates for genetic testing, according to Dr. Madigan. He presented a case report of a 39-year-old woman who had experienced sensory symptoms for years, with a sudden exacerbation along with allodynia following COVID-19 vaccination. Her cerebrospinal fluid protein was high and outside electromyography indicated mild demyelinating neuropathy, consistent with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). After her insurance denied IVIG treatment, she received solumedrol, but her symptoms worsened and she was referred to Dr. Madigan.

After 6 months of methotrexate treatment, her sensory symptoms had not improved, and she was referred for genetic testing, which revealed a truncating mutation of the MPZ gene. “What I learned from this case really was that, in a young patient with conduction slowing, you might be considering CIDP. It might actually be better to do genetic testing first as opposed to starting inflammatory neuropathy type treatments with respect to cost – the genetic tests costs $300 versus tens of thousands of dollars for IVIG – and for [patient] welfare as well,” said Dr. Madigan.

Specifically, when clinical signs point to inherited neuropathy and there is conduction slowing, “the biggest bang for your buck might to be to go straight to PMP22 deletion or duplication testing and see if you can get a diagnosis. If that is negative or the clinical features are not as you might suspect, then, if you have other supportive features such as a very young age or there’s predominance of motor or sensory symptoms, you could test more broadly with a panel. If both of these are negative, then you could consider exome sequencing if the clinical phenotype really is consistent with that,” said Dr. Madigan.
 

The treatment landscape

With a diagnosis in hand, it’s possible to turn to treatment options, and the CMT landscape is promising. Dr. Madigan’s group recently reviewed 286 CMT clinical trials published between 1999 and 2022, 86% of which were interventions. Most were procedures based on carpal or cubital tunnel release, extracorporeal shockwave therapy, or nerve hydrodissection.

The small-molecule drug combination PXT3003 (Pharnext) – comprising baclofen, naltrexone, and sorbitol – downregulated PMP22 mRNA expression and led to improved myelination in animal models. It is currently being studied in a phase 2 clinical trial. Other approaches include supplements, stem cells, anesthetics, and various devices.

Genetic therapy is in the preclinical stage, including gene replacement using adeno-associated virus (AAV) vectors, gene silencing using antisense oligonucleotides or RNA interference, and gene editing using CRISPR-Cas 9 approaches.

Gene replacement strategies include delivering a normal copy of the gene, a supportive gene, or a gene that delays or reduces axon degeneration. Gene silencing targets PMP22, while CRISPR-Cas9 gene editing aims for PMP22 or neurofilament light polypeptide (NEFL) gene knockout.

The most clinically advanced AAV program delivers neurotrophin-3 via the viral vector to the target muscle, which has been demonstrated to improve symptoms in a mouse model using a muscle-specific promoter. A phase 1/2a trial will test the approach in three patients.

In the antisense space, chemical advances have improved the profile of the RNA, including modifications that influence inflammatory properties, stability, and targeting of specific tissues through conjugation to specific lipids, proteins, or antibodies. A 2018 study sponsored by DTxPharma showed that the formulation could improve outcomes and histologic myelination in a mouse model. In the wake of Novartis’s acquisition of the technology, Dr. Madigan anticipates that clinical trials will likely begin in 2024.

Finally, CRISPR-Cas9 targeting of a promoter region that leads to PMP22 transcription improved remyelination and electrophysiological parameters after injection into the sciatic nerve of mice.
 

A need for genetic counseling

Advances in testing and therapies represent exciting developments, but they also create a need for genetic counselors, according to Dr. Madigan. His clinic has two certified genetic counselors who meet with patients and discuss testing options, including risks and benefits to family members. The counselors also provide psychological support and assist in shared decision-making. They also handle testing paperwork, which eases the burden on physicians.

If the tests are negative, the genetic counselor informs the patient and lets them know of any additional testing required. In case of a positive test, the genetic counselor informs the patient, but the physician also makes contact to discuss clinical implications of the result. “I think it’s working extremely well, and I would encourage all practices to begin to explore those options moving forward,” said Dr. Madigan.

During the Q&A session after the talk, an audience member noted that genetic counselors are not covered by insurance, which places a financial burden on providers to hire them. He noted that his facility has a large clinical genomics department that was able to fund the two counselors, though they are both part-time. “It wasn’t easy. I think there was at least a year of trying to work out how to do it in terms of finding positions and negotiating, but I think once it’s accomplished it’s incredibly cost effective in terms of getting patients what they need from that perspective, and helping with the testing,” said Dr. Madigan.

Dr. Madigan reported no relevant financial disclosures.

PHOENIX – New therapies are on the horizon for genetic neuromuscular diseases, and this will raise both hopes for patients and challenges for neurologists. Following successful genetic treatments for ALS, hereditary amyloidosis, and spinal muscular atrophy, therapies for conditions like Charcot-Marie-Tooth (CMT) neuropathy are set to change neurology practice, according to Nicolas Madigan, MBBCh, PhD, who spoke at the 2023 annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine (AANEM).

“I think we will very soon be in a position to tell these patients that they might actually have a better treatment outcome with a genetic treatment than if they had a sporadic or inflammatory disorder,” said Dr. Madigan, who is an assistant professor of clinical research at Mayo Clinic, Rochester, N.Y.

To illustrate how genetic therapies are changing neurology practice, Dr. Madigan focused his talk on CMT neuropathy, which is the most common hereditary neuropathy and, as a result, has become a prime focus of gene therapy development. “In a city of about a million people, there will be 100-800 patients with one of these disorders,” said Dr. Madigan.
 

Case report illustrates a change in approach

There are more than 100 known genes that can contribute to CMT, but about 90% of patients harbor alterations in one of four genes: PMP22, GJB1, MFN2, and MPZ.

The trick is determining which patients are candidates for genetic testing, according to Dr. Madigan. He presented a case report of a 39-year-old woman who had experienced sensory symptoms for years, with a sudden exacerbation along with allodynia following COVID-19 vaccination. Her cerebrospinal fluid protein was high and outside electromyography indicated mild demyelinating neuropathy, consistent with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). After her insurance denied IVIG treatment, she received solumedrol, but her symptoms worsened and she was referred to Dr. Madigan.

After 6 months of methotrexate treatment, her sensory symptoms had not improved, and she was referred for genetic testing, which revealed a truncating mutation of the MPZ gene. “What I learned from this case really was that, in a young patient with conduction slowing, you might be considering CIDP. It might actually be better to do genetic testing first as opposed to starting inflammatory neuropathy type treatments with respect to cost – the genetic tests costs $300 versus tens of thousands of dollars for IVIG – and for [patient] welfare as well,” said Dr. Madigan.

Specifically, when clinical signs point to inherited neuropathy and there is conduction slowing, “the biggest bang for your buck might to be to go straight to PMP22 deletion or duplication testing and see if you can get a diagnosis. If that is negative or the clinical features are not as you might suspect, then, if you have other supportive features such as a very young age or there’s predominance of motor or sensory symptoms, you could test more broadly with a panel. If both of these are negative, then you could consider exome sequencing if the clinical phenotype really is consistent with that,” said Dr. Madigan.
 

The treatment landscape

With a diagnosis in hand, it’s possible to turn to treatment options, and the CMT landscape is promising. Dr. Madigan’s group recently reviewed 286 CMT clinical trials published between 1999 and 2022, 86% of which were interventions. Most were procedures based on carpal or cubital tunnel release, extracorporeal shockwave therapy, or nerve hydrodissection.

The small-molecule drug combination PXT3003 (Pharnext) – comprising baclofen, naltrexone, and sorbitol – downregulated PMP22 mRNA expression and led to improved myelination in animal models. It is currently being studied in a phase 2 clinical trial. Other approaches include supplements, stem cells, anesthetics, and various devices.

Genetic therapy is in the preclinical stage, including gene replacement using adeno-associated virus (AAV) vectors, gene silencing using antisense oligonucleotides or RNA interference, and gene editing using CRISPR-Cas 9 approaches.

Gene replacement strategies include delivering a normal copy of the gene, a supportive gene, or a gene that delays or reduces axon degeneration. Gene silencing targets PMP22, while CRISPR-Cas9 gene editing aims for PMP22 or neurofilament light polypeptide (NEFL) gene knockout.

The most clinically advanced AAV program delivers neurotrophin-3 via the viral vector to the target muscle, which has been demonstrated to improve symptoms in a mouse model using a muscle-specific promoter. A phase 1/2a trial will test the approach in three patients.

In the antisense space, chemical advances have improved the profile of the RNA, including modifications that influence inflammatory properties, stability, and targeting of specific tissues through conjugation to specific lipids, proteins, or antibodies. A 2018 study sponsored by DTxPharma showed that the formulation could improve outcomes and histologic myelination in a mouse model. In the wake of Novartis’s acquisition of the technology, Dr. Madigan anticipates that clinical trials will likely begin in 2024.

Finally, CRISPR-Cas9 targeting of a promoter region that leads to PMP22 transcription improved remyelination and electrophysiological parameters after injection into the sciatic nerve of mice.
 

A need for genetic counseling

Advances in testing and therapies represent exciting developments, but they also create a need for genetic counselors, according to Dr. Madigan. His clinic has two certified genetic counselors who meet with patients and discuss testing options, including risks and benefits to family members. The counselors also provide psychological support and assist in shared decision-making. They also handle testing paperwork, which eases the burden on physicians.

If the tests are negative, the genetic counselor informs the patient and lets them know of any additional testing required. In case of a positive test, the genetic counselor informs the patient, but the physician also makes contact to discuss clinical implications of the result. “I think it’s working extremely well, and I would encourage all practices to begin to explore those options moving forward,” said Dr. Madigan.

During the Q&A session after the talk, an audience member noted that genetic counselors are not covered by insurance, which places a financial burden on providers to hire them. He noted that his facility has a large clinical genomics department that was able to fund the two counselors, though they are both part-time. “It wasn’t easy. I think there was at least a year of trying to work out how to do it in terms of finding positions and negotiating, but I think once it’s accomplished it’s incredibly cost effective in terms of getting patients what they need from that perspective, and helping with the testing,” said Dr. Madigan.

Dr. Madigan reported no relevant financial disclosures.

PHOENIX – New therapies are on the horizon for genetic neuromuscular diseases, and this will raise both hopes for patients and challenges for neurologists. Following successful genetic treatments for ALS, hereditary amyloidosis, and spinal muscular atrophy, therapies for conditions like Charcot-Marie-Tooth (CMT) neuropathy are set to change neurology practice, according to Nicolas Madigan, MBBCh, PhD, who spoke at the 2023 annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine (AANEM).

“I think we will very soon be in a position to tell these patients that they might actually have a better treatment outcome with a genetic treatment than if they had a sporadic or inflammatory disorder,” said Dr. Madigan, who is an assistant professor of clinical research at Mayo Clinic, Rochester, N.Y.

To illustrate how genetic therapies are changing neurology practice, Dr. Madigan focused his talk on CMT neuropathy, which is the most common hereditary neuropathy and, as a result, has become a prime focus of gene therapy development. “In a city of about a million people, there will be 100-800 patients with one of these disorders,” said Dr. Madigan.
 

Case report illustrates a change in approach

There are more than 100 known genes that can contribute to CMT, but about 90% of patients harbor alterations in one of four genes: PMP22, GJB1, MFN2, and MPZ.

The trick is determining which patients are candidates for genetic testing, according to Dr. Madigan. He presented a case report of a 39-year-old woman who had experienced sensory symptoms for years, with a sudden exacerbation along with allodynia following COVID-19 vaccination. Her cerebrospinal fluid protein was high and outside electromyography indicated mild demyelinating neuropathy, consistent with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). After her insurance denied IVIG treatment, she received solumedrol, but her symptoms worsened and she was referred to Dr. Madigan.

After 6 months of methotrexate treatment, her sensory symptoms had not improved, and she was referred for genetic testing, which revealed a truncating mutation of the MPZ gene. “What I learned from this case really was that, in a young patient with conduction slowing, you might be considering CIDP. It might actually be better to do genetic testing first as opposed to starting inflammatory neuropathy type treatments with respect to cost – the genetic tests costs $300 versus tens of thousands of dollars for IVIG – and for [patient] welfare as well,” said Dr. Madigan.

Specifically, when clinical signs point to inherited neuropathy and there is conduction slowing, “the biggest bang for your buck might to be to go straight to PMP22 deletion or duplication testing and see if you can get a diagnosis. If that is negative or the clinical features are not as you might suspect, then, if you have other supportive features such as a very young age or there’s predominance of motor or sensory symptoms, you could test more broadly with a panel. If both of these are negative, then you could consider exome sequencing if the clinical phenotype really is consistent with that,” said Dr. Madigan.
 

The treatment landscape

With a diagnosis in hand, it’s possible to turn to treatment options, and the CMT landscape is promising. Dr. Madigan’s group recently reviewed 286 CMT clinical trials published between 1999 and 2022, 86% of which were interventions. Most were procedures based on carpal or cubital tunnel release, extracorporeal shockwave therapy, or nerve hydrodissection.

The small-molecule drug combination PXT3003 (Pharnext) – comprising baclofen, naltrexone, and sorbitol – downregulated PMP22 mRNA expression and led to improved myelination in animal models. It is currently being studied in a phase 2 clinical trial. Other approaches include supplements, stem cells, anesthetics, and various devices.

Genetic therapy is in the preclinical stage, including gene replacement using adeno-associated virus (AAV) vectors, gene silencing using antisense oligonucleotides or RNA interference, and gene editing using CRISPR-Cas 9 approaches.

Gene replacement strategies include delivering a normal copy of the gene, a supportive gene, or a gene that delays or reduces axon degeneration. Gene silencing targets PMP22, while CRISPR-Cas9 gene editing aims for PMP22 or neurofilament light polypeptide (NEFL) gene knockout.

The most clinically advanced AAV program delivers neurotrophin-3 via the viral vector to the target muscle, which has been demonstrated to improve symptoms in a mouse model using a muscle-specific promoter. A phase 1/2a trial will test the approach in three patients.

In the antisense space, chemical advances have improved the profile of the RNA, including modifications that influence inflammatory properties, stability, and targeting of specific tissues through conjugation to specific lipids, proteins, or antibodies. A 2018 study sponsored by DTxPharma showed that the formulation could improve outcomes and histologic myelination in a mouse model. In the wake of Novartis’s acquisition of the technology, Dr. Madigan anticipates that clinical trials will likely begin in 2024.

Finally, CRISPR-Cas9 targeting of a promoter region that leads to PMP22 transcription improved remyelination and electrophysiological parameters after injection into the sciatic nerve of mice.
 

A need for genetic counseling

Advances in testing and therapies represent exciting developments, but they also create a need for genetic counselors, according to Dr. Madigan. His clinic has two certified genetic counselors who meet with patients and discuss testing options, including risks and benefits to family members. The counselors also provide psychological support and assist in shared decision-making. They also handle testing paperwork, which eases the burden on physicians.

If the tests are negative, the genetic counselor informs the patient and lets them know of any additional testing required. In case of a positive test, the genetic counselor informs the patient, but the physician also makes contact to discuss clinical implications of the result. “I think it’s working extremely well, and I would encourage all practices to begin to explore those options moving forward,” said Dr. Madigan.

During the Q&A session after the talk, an audience member noted that genetic counselors are not covered by insurance, which places a financial burden on providers to hire them. He noted that his facility has a large clinical genomics department that was able to fund the two counselors, though they are both part-time. “It wasn’t easy. I think there was at least a year of trying to work out how to do it in terms of finding positions and negotiating, but I think once it’s accomplished it’s incredibly cost effective in terms of getting patients what they need from that perspective, and helping with the testing,” said Dr. Madigan.

Dr. Madigan reported no relevant financial disclosures.

PHOENIX – Open-label extension studies of two neonatal Fc receptor–blocking antibodies showed good safety and efficacy in patients with myasthenia gravis (MG). The two drugs, rozanolixizumab (Rystiggo, UCB) and efgartigimod PH20 (Vyvgart, Argenx SE), received Food and Drug Administration approval in June 2023 and December 2021, respectively, for the treatment of MG.

The neonatal Fc receptor binds to IgG within cells and recycles it back into the blood, leading to increased serum levels. The antibodies bind to the neonatal Fc receptor and promote its degradation, therefore preventing IgG recycling without interfering with its production. They do not affect the levels of other immunoglobulin isotypes.

At the 2023 annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine (AANEM), researchers presented data from an open-label extension study following the phase 3 MycarinG trial of rozanolixizumab and the ADAPT-SC+ study of efgartigimod.

In the MycarinG study, rozanolixizumab “showed both statistically significant and clinically meaningful improvements in multiple endpoints,” said Vera Bril, MD, during a presentation of the results.

Rozanolixizumab is approved for MG patients who are anti–acetylcholine receptor (AchR) or anti–muscle-specific tyrosine kinase (MuSK) antibody positive. Efgartigimod is approved for MG patients who are AChR positive.

After completing MycarinG, patients were eligible to enroll in one of two open-label studies, one of each dose.

The new efficacy analysis focused on 110 patients who underwent two or more consecutive symptom-driven treatment cycles. A safety analysis focused on 188 patients who received at least one cycle of treatment.

“The post hoc analysis showed that the clinically meaningful improvements in the generalized myasthenia gravis symptoms were maintained over time for the cohort across rozanolixizumab cycles, while individual patients move through the consecutive treatment cycles, rozanolixizumab had an acceptable safety profile that was maintained across repeated treatments cycles. This is consistent with previous results of rozanolixizumab,” said Dr. Bril, who is a clinical investigator at University of Toronto
 

A reduction in steroid use?

During the Q&A session, George Small, MD, asked if the study had shown a reduction in steroid use among patients with MG.

As clinical associate director of neurology at Allegheny Medical Center, Pittsburgh, he has overseen the care of several hundred patients with generalized MG, as well as participated in clinical trials. “Many physicians use steroids for very quick responses in their patients. I love steroids and I hate steroids. I’ve helped save people’s lives with them, but I’ve also probably hastened their demise, unfortunately, because of the long-term side effects of the medications. Many neurologists in the community will over-utilize steroids because they don’t have access to these more expensive therapies. I look forward to both using these medications more as they become FDA approved and being an advocate for them, because it is my belief that they help decrease the use of steroids,” said Dr. Small in an interview.

Even if new medications do reduce steroid use, there remains a hurdle with insurance companies. “I’ve felt I’ve been forced to use treatments that I know may not be efficacious in the short term in order to get authorization for more expensive therapies that I use now. I’ve had patients admitted to the hospital as I’ve tried to jump through hoops that the insurance companies demanded,” said Dr. Small.
 

Clinical improvements seen

In the MycarinG study, patients received weekly injections of 7 mg/kg, 10 mg/kg rozanolixizumab, or placebo over a 6-week period. Both treatment groups had reductions in Myasthenia Gravis Activities of Daily Living (MG-ADL) scores compared with placebo.

MG-ADL and Quantitative Myasthenia Gravis (QMG) scores were consistent across treatment cycles. The mean MG-ADL score dropped by about 4 points at week 6. At around week 10, the mean improvement declined to 2 points, and then by week 14 it increased to 3 points, where it remained consistent out to 50 weeks. A similar pattern was seen in QMG scores, with an approximate 5-point drop at 6 weeks, then about a 1.5-point improvement at 10 weeks, then a mean decrease of around 4 points that stayed stable out to 50 weeks.

Over all cycles of treatment, 89.9% of patients experienced a treatment-emergent adverse event, including 22.3% who had a serious TEAE; the study dropout rate because of TEAEs was 15.4%.

In the ADAPT-SC study, 110 patients were randomized to 10 mg/kg intravenous efgartigimod or 1,000 mg efgartigimod PH20, which is formulated with recombinant human hyaluronidase to allow for rapid administration of larger volumes. After completion of ADAPT-SC, 105 patients from both groups and an additional 79 patients entered the open-label extension study with 1,000 mg efgartigimod PH20.

The study included 141 patients who were AChR-Ab positive and 38 who were AChR-Ab negative. In the first cycle, 34.6% experienced an injection-site reaction, which steadily dropped to 11.5% by the sixth cycle. After each cycle of treatment, the mean change in MG-ADL from study baseline at week 4 was between 4.1 and 4.7 points. The mean change in Myasthenia Gravis Quality of Life 15-Item Questionnaire revisited from study baseline at week 4 was between 5.1 and 6.5 points. The mean change in EuroQoL 5-dimension, 5-level visual analog scale was between 12.3 and 16.0 points at week 4.

MyCarinG was funded by UCB Pharma. ADAPT-SC was funded by Argenx SE. Dr. Bril has financial relationships with Behring, Argenyx, Alexion, Immunovant, Alnylam, Akcea, Takeda, Sanofi, Ionis, Roche, Novo Nordisk, Octapharma, Momenta, Pfizer, CSL Behring, Grifols, Powell Mansfield, UCB, and Viela Bio. Dr. Small is on the speaker’s bureau for Alexion.

PHOENIX – Open-label extension studies of two neonatal Fc receptor–blocking antibodies showed good safety and efficacy in patients with myasthenia gravis (MG). The two drugs, rozanolixizumab (Rystiggo, UCB) and efgartigimod PH20 (Vyvgart, Argenx SE), received Food and Drug Administration approval in June 2023 and December 2021, respectively, for the treatment of MG.

The neonatal Fc receptor binds to IgG within cells and recycles it back into the blood, leading to increased serum levels. The antibodies bind to the neonatal Fc receptor and promote its degradation, therefore preventing IgG recycling without interfering with its production. They do not affect the levels of other immunoglobulin isotypes.

At the 2023 annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine (AANEM), researchers presented data from an open-label extension study following the phase 3 MycarinG trial of rozanolixizumab and the ADAPT-SC+ study of efgartigimod.

In the MycarinG study, rozanolixizumab “showed both statistically significant and clinically meaningful improvements in multiple endpoints,” said Vera Bril, MD, during a presentation of the results.

Rozanolixizumab is approved for MG patients who are anti–acetylcholine receptor (AchR) or anti–muscle-specific tyrosine kinase (MuSK) antibody positive. Efgartigimod is approved for MG patients who are AChR positive.

After completing MycarinG, patients were eligible to enroll in one of two open-label studies, one of each dose.

The new efficacy analysis focused on 110 patients who underwent two or more consecutive symptom-driven treatment cycles. A safety analysis focused on 188 patients who received at least one cycle of treatment.

“The post hoc analysis showed that the clinically meaningful improvements in the generalized myasthenia gravis symptoms were maintained over time for the cohort across rozanolixizumab cycles, while individual patients move through the consecutive treatment cycles, rozanolixizumab had an acceptable safety profile that was maintained across repeated treatments cycles. This is consistent with previous results of rozanolixizumab,” said Dr. Bril, who is a clinical investigator at University of Toronto
 

A reduction in steroid use?

During the Q&A session, George Small, MD, asked if the study had shown a reduction in steroid use among patients with MG.

As clinical associate director of neurology at Allegheny Medical Center, Pittsburgh, he has overseen the care of several hundred patients with generalized MG, as well as participated in clinical trials. “Many physicians use steroids for very quick responses in their patients. I love steroids and I hate steroids. I’ve helped save people’s lives with them, but I’ve also probably hastened their demise, unfortunately, because of the long-term side effects of the medications. Many neurologists in the community will over-utilize steroids because they don’t have access to these more expensive therapies. I look forward to both using these medications more as they become FDA approved and being an advocate for them, because it is my belief that they help decrease the use of steroids,” said Dr. Small in an interview.

Even if new medications do reduce steroid use, there remains a hurdle with insurance companies. “I’ve felt I’ve been forced to use treatments that I know may not be efficacious in the short term in order to get authorization for more expensive therapies that I use now. I’ve had patients admitted to the hospital as I’ve tried to jump through hoops that the insurance companies demanded,” said Dr. Small.
 

Clinical improvements seen

In the MycarinG study, patients received weekly injections of 7 mg/kg, 10 mg/kg rozanolixizumab, or placebo over a 6-week period. Both treatment groups had reductions in Myasthenia Gravis Activities of Daily Living (MG-ADL) scores compared with placebo.

MG-ADL and Quantitative Myasthenia Gravis (QMG) scores were consistent across treatment cycles. The mean MG-ADL score dropped by about 4 points at week 6. At around week 10, the mean improvement declined to 2 points, and then by week 14 it increased to 3 points, where it remained consistent out to 50 weeks. A similar pattern was seen in QMG scores, with an approximate 5-point drop at 6 weeks, then about a 1.5-point improvement at 10 weeks, then a mean decrease of around 4 points that stayed stable out to 50 weeks.

Over all cycles of treatment, 89.9% of patients experienced a treatment-emergent adverse event, including 22.3% who had a serious TEAE; the study dropout rate because of TEAEs was 15.4%.

In the ADAPT-SC study, 110 patients were randomized to 10 mg/kg intravenous efgartigimod or 1,000 mg efgartigimod PH20, which is formulated with recombinant human hyaluronidase to allow for rapid administration of larger volumes. After completion of ADAPT-SC, 105 patients from both groups and an additional 79 patients entered the open-label extension study with 1,000 mg efgartigimod PH20.

The study included 141 patients who were AChR-Ab positive and 38 who were AChR-Ab negative. In the first cycle, 34.6% experienced an injection-site reaction, which steadily dropped to 11.5% by the sixth cycle. After each cycle of treatment, the mean change in MG-ADL from study baseline at week 4 was between 4.1 and 4.7 points. The mean change in Myasthenia Gravis Quality of Life 15-Item Questionnaire revisited from study baseline at week 4 was between 5.1 and 6.5 points. The mean change in EuroQoL 5-dimension, 5-level visual analog scale was between 12.3 and 16.0 points at week 4.

MyCarinG was funded by UCB Pharma. ADAPT-SC was funded by Argenx SE. Dr. Bril has financial relationships with Behring, Argenyx, Alexion, Immunovant, Alnylam, Akcea, Takeda, Sanofi, Ionis, Roche, Novo Nordisk, Octapharma, Momenta, Pfizer, CSL Behring, Grifols, Powell Mansfield, UCB, and Viela Bio. Dr. Small is on the speaker’s bureau for Alexion.

PHOENIX – Open-label extension studies of two neonatal Fc receptor–blocking antibodies showed good safety and efficacy in patients with myasthenia gravis (MG). The two drugs, rozanolixizumab (Rystiggo, UCB) and efgartigimod PH20 (Vyvgart, Argenx SE), received Food and Drug Administration approval in June 2023 and December 2021, respectively, for the treatment of MG.

The neonatal Fc receptor binds to IgG within cells and recycles it back into the blood, leading to increased serum levels. The antibodies bind to the neonatal Fc receptor and promote its degradation, therefore preventing IgG recycling without interfering with its production. They do not affect the levels of other immunoglobulin isotypes.

At the 2023 annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine (AANEM), researchers presented data from an open-label extension study following the phase 3 MycarinG trial of rozanolixizumab and the ADAPT-SC+ study of efgartigimod.

In the MycarinG study, rozanolixizumab “showed both statistically significant and clinically meaningful improvements in multiple endpoints,” said Vera Bril, MD, during a presentation of the results.

Rozanolixizumab is approved for MG patients who are anti–acetylcholine receptor (AchR) or anti–muscle-specific tyrosine kinase (MuSK) antibody positive. Efgartigimod is approved for MG patients who are AChR positive.

After completing MycarinG, patients were eligible to enroll in one of two open-label studies, one of each dose.

The new efficacy analysis focused on 110 patients who underwent two or more consecutive symptom-driven treatment cycles. A safety analysis focused on 188 patients who received at least one cycle of treatment.

“The post hoc analysis showed that the clinically meaningful improvements in the generalized myasthenia gravis symptoms were maintained over time for the cohort across rozanolixizumab cycles, while individual patients move through the consecutive treatment cycles, rozanolixizumab had an acceptable safety profile that was maintained across repeated treatments cycles. This is consistent with previous results of rozanolixizumab,” said Dr. Bril, who is a clinical investigator at University of Toronto
 

A reduction in steroid use?

During the Q&A session, George Small, MD, asked if the study had shown a reduction in steroid use among patients with MG.

As clinical associate director of neurology at Allegheny Medical Center, Pittsburgh, he has overseen the care of several hundred patients with generalized MG, as well as participated in clinical trials. “Many physicians use steroids for very quick responses in their patients. I love steroids and I hate steroids. I’ve helped save people’s lives with them, but I’ve also probably hastened their demise, unfortunately, because of the long-term side effects of the medications. Many neurologists in the community will over-utilize steroids because they don’t have access to these more expensive therapies. I look forward to both using these medications more as they become FDA approved and being an advocate for them, because it is my belief that they help decrease the use of steroids,” said Dr. Small in an interview.

Even if new medications do reduce steroid use, there remains a hurdle with insurance companies. “I’ve felt I’ve been forced to use treatments that I know may not be efficacious in the short term in order to get authorization for more expensive therapies that I use now. I’ve had patients admitted to the hospital as I’ve tried to jump through hoops that the insurance companies demanded,” said Dr. Small.
 

Clinical improvements seen

In the MycarinG study, patients received weekly injections of 7 mg/kg, 10 mg/kg rozanolixizumab, or placebo over a 6-week period. Both treatment groups had reductions in Myasthenia Gravis Activities of Daily Living (MG-ADL) scores compared with placebo.

MG-ADL and Quantitative Myasthenia Gravis (QMG) scores were consistent across treatment cycles. The mean MG-ADL score dropped by about 4 points at week 6. At around week 10, the mean improvement declined to 2 points, and then by week 14 it increased to 3 points, where it remained consistent out to 50 weeks. A similar pattern was seen in QMG scores, with an approximate 5-point drop at 6 weeks, then about a 1.5-point improvement at 10 weeks, then a mean decrease of around 4 points that stayed stable out to 50 weeks.

Over all cycles of treatment, 89.9% of patients experienced a treatment-emergent adverse event, including 22.3% who had a serious TEAE; the study dropout rate because of TEAEs was 15.4%.

In the ADAPT-SC study, 110 patients were randomized to 10 mg/kg intravenous efgartigimod or 1,000 mg efgartigimod PH20, which is formulated with recombinant human hyaluronidase to allow for rapid administration of larger volumes. After completion of ADAPT-SC, 105 patients from both groups and an additional 79 patients entered the open-label extension study with 1,000 mg efgartigimod PH20.

The study included 141 patients who were AChR-Ab positive and 38 who were AChR-Ab negative. In the first cycle, 34.6% experienced an injection-site reaction, which steadily dropped to 11.5% by the sixth cycle. After each cycle of treatment, the mean change in MG-ADL from study baseline at week 4 was between 4.1 and 4.7 points. The mean change in Myasthenia Gravis Quality of Life 15-Item Questionnaire revisited from study baseline at week 4 was between 5.1 and 6.5 points. The mean change in EuroQoL 5-dimension, 5-level visual analog scale was between 12.3 and 16.0 points at week 4.

MyCarinG was funded by UCB Pharma. ADAPT-SC was funded by Argenx SE. Dr. Bril has financial relationships with Behring, Argenyx, Alexion, Immunovant, Alnylam, Akcea, Takeda, Sanofi, Ionis, Roche, Novo Nordisk, Octapharma, Momenta, Pfizer, CSL Behring, Grifols, Powell Mansfield, UCB, and Viela Bio. Dr. Small is on the speaker’s bureau for Alexion.