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Anti-MOG antibodies associated with non-MS, monophasic demyelinating disease in young children
BERLIN – In children with an incident acquired demyelinating episode, the presence of antibodies against myelin oligodendrocyte glycoprotein (MOG) weighs against an eventual diagnosis of multiple sclerosis, especially if the child is younger than 11 years.
“Anti-MOG antibodies are present in about 30% of children with acquired demyelinating syndromes,” Giulia Fadda, MD, said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis. “About 80% experience a monophasic disease course.”
The antibodies are found in almost all children who have a relapsing non-MS demyelinating disease, said Dr. Fadda, who is a postdoctoral research fellow at the University of Pennsylvania, Philadelphia. But when the antibodies are present in children with an MS diagnosis, they identify a very specific subset with atypical clinical and imaging features.
The large prospective Canadian Pediatric Demyelinating Disease Study provided the sample for the study she presented at ECTRIMS. Children are recruited into the study soon after a first demyelinating event, and they are followed clinically, serologically, and with regular brain MRI.
The cohort in Dr. Fadda’s study comprised 275 children who were a mean of about 11 years old at symptom onset. The mean clinical follow-up was 6.7 years; the mean serologic follow-up, 4 years, and the mean imaging follow-up, 3.5 years. The study examined 1,368 serum samples and 1,459 MRI scans.
Overall, 32% of the children were positive for anti-MOG antibodies. Positivity was not associated with sex, but children with antibodies were significantly younger than those without (7 vs. 12 years). In fact, 77% of anti-MOG–positive children were younger than 11 years; just 15% of older children were positive for the antibodies.
Anti-MOG positivity was also associated with certain clinical phenotypes. Among positive children, 40% presented with optic neuritis, 37% with acute disseminated encephalomyelitis, and 14% with transverse myelitis; the rest had other phenotypes. Optic neuritis was significantly less common among antibody-negative patients (22%), as was encephalomyelitis (17%). Transverse myelitis was significantly more common (31%).
The analysis of MRI scans was stratified according to age younger than 11 years and 11 years and older. “The first thing we noticed among the younger MOG-positive children is that they had a high number of lesions, which were more commonly ill-defined, diffuse, and bilateral,” Dr. Fadda said. “Almost all the brain areas were affected, with a slight preponderance of thalamic and juxtacortical lesions. Among the MOG-negative children, lesions were more often perpendicular to the major axis of the corpus callosum.”
Among the older MOG antibody–positive children, the diffuse pattern was rarer, and the lesions were frequently cerebellar. “But by far, the features that best differentiated positivity from negativity were black holes and enhancing lesions, which we saw in a high proportion of children without the antibodies” at 73% and 49%, respectively.
Over a mean imaging follow-up period of 4 years, lesions were more likely to resolve completely in antibody-positive children than in those without antibodies (50% vs. 21%). Serologically, children who were MOG-antibody negative at baseline were likely to stay that way, with 99% remaining seronegative. Positive children, on the other hand, were significantly more likely to change serologic status, with 56% turning negative and 8% serologically fluctuating over the follow-up period; only 36% remained persistently seropositive. Persistent positive status was significantly associated with younger age (7 vs. 9 years) and an optic neuritis presentation (62% vs. 27%).
Most children (81%) who were antibody positive at baseline experienced no relapses. Among the 16 children who did experience a clinical relapse, the mean time to a second event was about 1 year. Nine of these children stayed persistently positive, while five seroconverted and two had fluctuating status.
Of the 60 antibody-positive children who had a monophasic course, 23 were persistently positive, 34 seroconverted, and 3 had fluctuating serology.
Eventually, 54 children received an MS diagnosis. Of these, 83% were antibody negative at baseline. Ten children received a diagnosis of a relapsing non-MS demyelinating disorder; of these, 91% were antibody positive at baseline.
Dr. Fadda disclosed relationships with Atara Biotherapeutic and Sanofi-Genzyme.
SOURCE: Waters P et al. Mult Scler. 2018;24(S2):29-30, Abstract 65.
BERLIN – In children with an incident acquired demyelinating episode, the presence of antibodies against myelin oligodendrocyte glycoprotein (MOG) weighs against an eventual diagnosis of multiple sclerosis, especially if the child is younger than 11 years.
“Anti-MOG antibodies are present in about 30% of children with acquired demyelinating syndromes,” Giulia Fadda, MD, said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis. “About 80% experience a monophasic disease course.”
The antibodies are found in almost all children who have a relapsing non-MS demyelinating disease, said Dr. Fadda, who is a postdoctoral research fellow at the University of Pennsylvania, Philadelphia. But when the antibodies are present in children with an MS diagnosis, they identify a very specific subset with atypical clinical and imaging features.
The large prospective Canadian Pediatric Demyelinating Disease Study provided the sample for the study she presented at ECTRIMS. Children are recruited into the study soon after a first demyelinating event, and they are followed clinically, serologically, and with regular brain MRI.
The cohort in Dr. Fadda’s study comprised 275 children who were a mean of about 11 years old at symptom onset. The mean clinical follow-up was 6.7 years; the mean serologic follow-up, 4 years, and the mean imaging follow-up, 3.5 years. The study examined 1,368 serum samples and 1,459 MRI scans.
Overall, 32% of the children were positive for anti-MOG antibodies. Positivity was not associated with sex, but children with antibodies were significantly younger than those without (7 vs. 12 years). In fact, 77% of anti-MOG–positive children were younger than 11 years; just 15% of older children were positive for the antibodies.
Anti-MOG positivity was also associated with certain clinical phenotypes. Among positive children, 40% presented with optic neuritis, 37% with acute disseminated encephalomyelitis, and 14% with transverse myelitis; the rest had other phenotypes. Optic neuritis was significantly less common among antibody-negative patients (22%), as was encephalomyelitis (17%). Transverse myelitis was significantly more common (31%).
The analysis of MRI scans was stratified according to age younger than 11 years and 11 years and older. “The first thing we noticed among the younger MOG-positive children is that they had a high number of lesions, which were more commonly ill-defined, diffuse, and bilateral,” Dr. Fadda said. “Almost all the brain areas were affected, with a slight preponderance of thalamic and juxtacortical lesions. Among the MOG-negative children, lesions were more often perpendicular to the major axis of the corpus callosum.”
Among the older MOG antibody–positive children, the diffuse pattern was rarer, and the lesions were frequently cerebellar. “But by far, the features that best differentiated positivity from negativity were black holes and enhancing lesions, which we saw in a high proportion of children without the antibodies” at 73% and 49%, respectively.
Over a mean imaging follow-up period of 4 years, lesions were more likely to resolve completely in antibody-positive children than in those without antibodies (50% vs. 21%). Serologically, children who were MOG-antibody negative at baseline were likely to stay that way, with 99% remaining seronegative. Positive children, on the other hand, were significantly more likely to change serologic status, with 56% turning negative and 8% serologically fluctuating over the follow-up period; only 36% remained persistently seropositive. Persistent positive status was significantly associated with younger age (7 vs. 9 years) and an optic neuritis presentation (62% vs. 27%).
Most children (81%) who were antibody positive at baseline experienced no relapses. Among the 16 children who did experience a clinical relapse, the mean time to a second event was about 1 year. Nine of these children stayed persistently positive, while five seroconverted and two had fluctuating status.
Of the 60 antibody-positive children who had a monophasic course, 23 were persistently positive, 34 seroconverted, and 3 had fluctuating serology.
Eventually, 54 children received an MS diagnosis. Of these, 83% were antibody negative at baseline. Ten children received a diagnosis of a relapsing non-MS demyelinating disorder; of these, 91% were antibody positive at baseline.
Dr. Fadda disclosed relationships with Atara Biotherapeutic and Sanofi-Genzyme.
SOURCE: Waters P et al. Mult Scler. 2018;24(S2):29-30, Abstract 65.
BERLIN – In children with an incident acquired demyelinating episode, the presence of antibodies against myelin oligodendrocyte glycoprotein (MOG) weighs against an eventual diagnosis of multiple sclerosis, especially if the child is younger than 11 years.
“Anti-MOG antibodies are present in about 30% of children with acquired demyelinating syndromes,” Giulia Fadda, MD, said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis. “About 80% experience a monophasic disease course.”
The antibodies are found in almost all children who have a relapsing non-MS demyelinating disease, said Dr. Fadda, who is a postdoctoral research fellow at the University of Pennsylvania, Philadelphia. But when the antibodies are present in children with an MS diagnosis, they identify a very specific subset with atypical clinical and imaging features.
The large prospective Canadian Pediatric Demyelinating Disease Study provided the sample for the study she presented at ECTRIMS. Children are recruited into the study soon after a first demyelinating event, and they are followed clinically, serologically, and with regular brain MRI.
The cohort in Dr. Fadda’s study comprised 275 children who were a mean of about 11 years old at symptom onset. The mean clinical follow-up was 6.7 years; the mean serologic follow-up, 4 years, and the mean imaging follow-up, 3.5 years. The study examined 1,368 serum samples and 1,459 MRI scans.
Overall, 32% of the children were positive for anti-MOG antibodies. Positivity was not associated with sex, but children with antibodies were significantly younger than those without (7 vs. 12 years). In fact, 77% of anti-MOG–positive children were younger than 11 years; just 15% of older children were positive for the antibodies.
Anti-MOG positivity was also associated with certain clinical phenotypes. Among positive children, 40% presented with optic neuritis, 37% with acute disseminated encephalomyelitis, and 14% with transverse myelitis; the rest had other phenotypes. Optic neuritis was significantly less common among antibody-negative patients (22%), as was encephalomyelitis (17%). Transverse myelitis was significantly more common (31%).
The analysis of MRI scans was stratified according to age younger than 11 years and 11 years and older. “The first thing we noticed among the younger MOG-positive children is that they had a high number of lesions, which were more commonly ill-defined, diffuse, and bilateral,” Dr. Fadda said. “Almost all the brain areas were affected, with a slight preponderance of thalamic and juxtacortical lesions. Among the MOG-negative children, lesions were more often perpendicular to the major axis of the corpus callosum.”
Among the older MOG antibody–positive children, the diffuse pattern was rarer, and the lesions were frequently cerebellar. “But by far, the features that best differentiated positivity from negativity were black holes and enhancing lesions, which we saw in a high proportion of children without the antibodies” at 73% and 49%, respectively.
Over a mean imaging follow-up period of 4 years, lesions were more likely to resolve completely in antibody-positive children than in those without antibodies (50% vs. 21%). Serologically, children who were MOG-antibody negative at baseline were likely to stay that way, with 99% remaining seronegative. Positive children, on the other hand, were significantly more likely to change serologic status, with 56% turning negative and 8% serologically fluctuating over the follow-up period; only 36% remained persistently seropositive. Persistent positive status was significantly associated with younger age (7 vs. 9 years) and an optic neuritis presentation (62% vs. 27%).
Most children (81%) who were antibody positive at baseline experienced no relapses. Among the 16 children who did experience a clinical relapse, the mean time to a second event was about 1 year. Nine of these children stayed persistently positive, while five seroconverted and two had fluctuating status.
Of the 60 antibody-positive children who had a monophasic course, 23 were persistently positive, 34 seroconverted, and 3 had fluctuating serology.
Eventually, 54 children received an MS diagnosis. Of these, 83% were antibody negative at baseline. Ten children received a diagnosis of a relapsing non-MS demyelinating disorder; of these, 91% were antibody positive at baseline.
Dr. Fadda disclosed relationships with Atara Biotherapeutic and Sanofi-Genzyme.
SOURCE: Waters P et al. Mult Scler. 2018;24(S2):29-30, Abstract 65.
REPORTING FROM ECTRIMS 2018
Key clinical point:
Major finding: Most children (81%) who were antibody positive at baseline experienced no relapses.
Study details: A cohort of 275 children from the prospective Canadian Pediatric Demyelinating Disease Study.
Disclosures: Dr. Fadda disclosed relationships with Atara Biotherapeutics and Sanofi-Genzyme.
Source: Waters P et al. Mult Scler. 2018;24(S2):29-30, Abstract 65.
FDA approves Primatene Mist return
After a long absence, Primatene Mist, an over-the-counter asthma inhaler removed from the market in 2011, is being reintroduced in a metered-dose inhaler with a new, environmentally friendly propellant.
But the inhaler’s comeback may prove as controversial as its removal. Respiratory medicine associations have taken issue with the Food and Drug Administration’s decision, warning patients that asthma is not a “do-it-yourself” disease that can be managed with over-the-counter medications.
The American College of Allergy, Asthma, and Immunology, American College of Chest Physicians, American Lung Association, American Thoracic Society, and the American Association of Asthma Educators have each individually protested the decision, and together sent a joint resolution to FDA decrying it. At the core of their protest are the facts that epinephrine is a symptomatic, not therapeutic, asthma treatment and that racemic epinephrine is not a not a recommended asthma treatment under the National Institutes of Health’s “Guidelines for the Diagnosis and Management of Asthma.”
CHEST has published the following statement: “The American College of Chest Physicians (CHEST) is disappointed with the FDA’s decision to approve over-the counter epinephrine (Primatene® Mist HFA) for the treatment of asthma. CHEST is a nonprofit organization dedicated to advancing best patient outcomes. Our membership of more than 19,000 members from around the world provides patient care in pulmonary, critical care, and sleep medicine.
Asthma is a serious and chronic condition with associated high health-care burden. Care for ALL patients with asthma should be under the guidance of a health-care provider. The majority of asthma patients requires treatment with a controller medication, which is only available by prescription. Frequent rescue inhaler use has been associated with increased morbidity and mortality. Over the counter availability of a reliever medication like Primatene Mist can endanger a patient’s wellbeing by providing temporary relief in symptoms, resulting in delay in seeking medical care.”
The inhaler was pulled from sales as part of an international pact to reduce ozone-depleting substances. The 1989 Montreal Protocol of Substances that Deplete the Ozone Layer and the Clean Air Act of 1990 targeted chlorofluorocarbons among those substances, and epinephrine inhalers that contained CFCs were phased out.
The new Primatene Mist HFA (Amphastar Pharmaceuticals) contains hydrofluoroalkane (HFA) propellants, which are permitted under current international and U.S. law. This puts Primatene in the same category with other inhalers, including albuterol and levalbuterol, which also use HFAs as propellants. Each dose delivers 125 mcg of epinephrine.
The inhaler itself has also been redesigned, according to Theresa Michele, MD, director of the FDA’s Division of Nonprescription Drug Products in the Center for Drug Evaluation and Research. The active ingredient is still epinephrine, albeit a smaller dose than found in the original 200-mcg mist. However, the inhaler needs to be activated before first use and cleaned every day after use to prevent a medication buildup. Like other metered-dose inhalers, it requires a priming spray before the inhalation dose, Dr. Michele noted in her online column.
“The inhaler also needs to be shaken and then sprayed once into the air before each use. It may seem strange to shake and spray the inhaler into the air each time before using it. But these two steps are critical to ensure that the medicine is properly mixed before each dose,” Dr. Michele wrote.
A public statement by FDA Commissioner Scott Gottlieb, MD, and Janet Woodcock, MD, director of the Center for Drug Evaluation and Research, asserted that the inhaler fills a clinical gap for patients with mild to moderate intermittent asthma.
“The scientific information we reviewed to approve the new version of OTC Primatene Mist shows there is a narrow population of those diagnosed with asthma that may benefit from having access to this type of OTC asthma inhaler. But the product has certain cautions. Making sure that patients can understand and apply the instructions for use was a critical consideration for the FDA. The new product is only appropriate for those with a diagnosis of mild, intermittent asthma. Patients with more severe asthma should not rely on it. Instead, they should be working with their health care provider to ensure an appropriate treatment plan for their condition.”
Before this approval, Amphastar had unsuccessfully brought the reformulated Primatene before FDA several times. The move to finally reinstate it comes after a long, and sometimes contentious, debate among patients and FDA’s Nonprescription Drugs and Pulmonary-Allergy Drugs advisory committee. A quick Internet or Facebook search brings up dozens of stories from patients who say they effectively managed their mild to moderate asthma for years with Primatene. Typically, the stories describe changing to prescription asthma medications that, for some, run into the hundreds of dollars per month. Supporters often negatively compare decades of using the inexpensive Primatene with no ill effects to their recent experiences using prescription corticosteroid inhalers.
It was 4 years ago when Amphastar first appeared before the advisory committee with the reformulated inhaler and positive safety and efficacy data. Although agreeing with the efficacy data, the advisory committee voted against approval, because some felt that asthma should always be managed by a physician; an OTC bronchodilator encouraged self-medicating and discouraged patients from seeking medical care, they said.
“On the one hand, it has been stated that a quick-relief medication available OTC is needed for use in low-income, elderly, and uninsured individuals who might otherwise not have access to treatment or be able to see a health care practitioner,” FDA documents noted. “In contrast, there is also a concern that because asthma is a potentially life-threatening condition that should be diagnosed and treated by a health care professional, availability of an OTC bronchodilator product may discourage consumers from seeking appropriate care, resulting in worse asthma outcomes.”
Two years later, the company received another blow to Primatene program. FDA’s Complete Response Letter required Amphastar to make additional changes to the packaging and run a consumer product safety study, intended to show that people could learn to use the metered-dose inhaler correctly.
In Amphastar’s 2018 first-quarter report, however, company CEO Jack Zhang, PhD, finally shared some good news. “We are pleased to announce that we have resubmitted our NDA for Primatene Mist after receiving good results from our recent human factors study. While we don’t have a Prescription Free User Drug Act [PDUFA] date yet, we plan to begin producing inventory in preparation for a launch.”
That day arrived on Nov. 8, when the PDUFA was granted. In their public letter, Dr. Gottlieb and Dr. Woodcock acknowledged the long and difficult approval path and offered reassurance that Primatene is safe and effective.
“For the right patient, our analysis of the data, including new information that was developed since this product was previously on the market, shows that there are no serious safety concerns when Primatene Mist is used as directed. The product is appropriate for mild symptoms of intermittent asthma, however, even patients with mild asthma can have severe exacerbations – so it’s still important to consult a health care provider about appropriate care and have their condition reassessed. And, of course, all patients who experience severe exacerbations should go to the emergency room right away.”
Primatene Mist HFA is intended for the temporary relief of mild symptoms of intermittent asthma (wheezing, tightness of chest, shortness of breath) in patients aged 12 years and older. It should not be considered a replacement for prescription asthma medications. It should be available in stores early next year.
After a long absence, Primatene Mist, an over-the-counter asthma inhaler removed from the market in 2011, is being reintroduced in a metered-dose inhaler with a new, environmentally friendly propellant.
But the inhaler’s comeback may prove as controversial as its removal. Respiratory medicine associations have taken issue with the Food and Drug Administration’s decision, warning patients that asthma is not a “do-it-yourself” disease that can be managed with over-the-counter medications.
The American College of Allergy, Asthma, and Immunology, American College of Chest Physicians, American Lung Association, American Thoracic Society, and the American Association of Asthma Educators have each individually protested the decision, and together sent a joint resolution to FDA decrying it. At the core of their protest are the facts that epinephrine is a symptomatic, not therapeutic, asthma treatment and that racemic epinephrine is not a not a recommended asthma treatment under the National Institutes of Health’s “Guidelines for the Diagnosis and Management of Asthma.”
CHEST has published the following statement: “The American College of Chest Physicians (CHEST) is disappointed with the FDA’s decision to approve over-the counter epinephrine (Primatene® Mist HFA) for the treatment of asthma. CHEST is a nonprofit organization dedicated to advancing best patient outcomes. Our membership of more than 19,000 members from around the world provides patient care in pulmonary, critical care, and sleep medicine.
Asthma is a serious and chronic condition with associated high health-care burden. Care for ALL patients with asthma should be under the guidance of a health-care provider. The majority of asthma patients requires treatment with a controller medication, which is only available by prescription. Frequent rescue inhaler use has been associated with increased morbidity and mortality. Over the counter availability of a reliever medication like Primatene Mist can endanger a patient’s wellbeing by providing temporary relief in symptoms, resulting in delay in seeking medical care.”
The inhaler was pulled from sales as part of an international pact to reduce ozone-depleting substances. The 1989 Montreal Protocol of Substances that Deplete the Ozone Layer and the Clean Air Act of 1990 targeted chlorofluorocarbons among those substances, and epinephrine inhalers that contained CFCs were phased out.
The new Primatene Mist HFA (Amphastar Pharmaceuticals) contains hydrofluoroalkane (HFA) propellants, which are permitted under current international and U.S. law. This puts Primatene in the same category with other inhalers, including albuterol and levalbuterol, which also use HFAs as propellants. Each dose delivers 125 mcg of epinephrine.
The inhaler itself has also been redesigned, according to Theresa Michele, MD, director of the FDA’s Division of Nonprescription Drug Products in the Center for Drug Evaluation and Research. The active ingredient is still epinephrine, albeit a smaller dose than found in the original 200-mcg mist. However, the inhaler needs to be activated before first use and cleaned every day after use to prevent a medication buildup. Like other metered-dose inhalers, it requires a priming spray before the inhalation dose, Dr. Michele noted in her online column.
“The inhaler also needs to be shaken and then sprayed once into the air before each use. It may seem strange to shake and spray the inhaler into the air each time before using it. But these two steps are critical to ensure that the medicine is properly mixed before each dose,” Dr. Michele wrote.
A public statement by FDA Commissioner Scott Gottlieb, MD, and Janet Woodcock, MD, director of the Center for Drug Evaluation and Research, asserted that the inhaler fills a clinical gap for patients with mild to moderate intermittent asthma.
“The scientific information we reviewed to approve the new version of OTC Primatene Mist shows there is a narrow population of those diagnosed with asthma that may benefit from having access to this type of OTC asthma inhaler. But the product has certain cautions. Making sure that patients can understand and apply the instructions for use was a critical consideration for the FDA. The new product is only appropriate for those with a diagnosis of mild, intermittent asthma. Patients with more severe asthma should not rely on it. Instead, they should be working with their health care provider to ensure an appropriate treatment plan for their condition.”
Before this approval, Amphastar had unsuccessfully brought the reformulated Primatene before FDA several times. The move to finally reinstate it comes after a long, and sometimes contentious, debate among patients and FDA’s Nonprescription Drugs and Pulmonary-Allergy Drugs advisory committee. A quick Internet or Facebook search brings up dozens of stories from patients who say they effectively managed their mild to moderate asthma for years with Primatene. Typically, the stories describe changing to prescription asthma medications that, for some, run into the hundreds of dollars per month. Supporters often negatively compare decades of using the inexpensive Primatene with no ill effects to their recent experiences using prescription corticosteroid inhalers.
It was 4 years ago when Amphastar first appeared before the advisory committee with the reformulated inhaler and positive safety and efficacy data. Although agreeing with the efficacy data, the advisory committee voted against approval, because some felt that asthma should always be managed by a physician; an OTC bronchodilator encouraged self-medicating and discouraged patients from seeking medical care, they said.
“On the one hand, it has been stated that a quick-relief medication available OTC is needed for use in low-income, elderly, and uninsured individuals who might otherwise not have access to treatment or be able to see a health care practitioner,” FDA documents noted. “In contrast, there is also a concern that because asthma is a potentially life-threatening condition that should be diagnosed and treated by a health care professional, availability of an OTC bronchodilator product may discourage consumers from seeking appropriate care, resulting in worse asthma outcomes.”
Two years later, the company received another blow to Primatene program. FDA’s Complete Response Letter required Amphastar to make additional changes to the packaging and run a consumer product safety study, intended to show that people could learn to use the metered-dose inhaler correctly.
In Amphastar’s 2018 first-quarter report, however, company CEO Jack Zhang, PhD, finally shared some good news. “We are pleased to announce that we have resubmitted our NDA for Primatene Mist after receiving good results from our recent human factors study. While we don’t have a Prescription Free User Drug Act [PDUFA] date yet, we plan to begin producing inventory in preparation for a launch.”
That day arrived on Nov. 8, when the PDUFA was granted. In their public letter, Dr. Gottlieb and Dr. Woodcock acknowledged the long and difficult approval path and offered reassurance that Primatene is safe and effective.
“For the right patient, our analysis of the data, including new information that was developed since this product was previously on the market, shows that there are no serious safety concerns when Primatene Mist is used as directed. The product is appropriate for mild symptoms of intermittent asthma, however, even patients with mild asthma can have severe exacerbations – so it’s still important to consult a health care provider about appropriate care and have their condition reassessed. And, of course, all patients who experience severe exacerbations should go to the emergency room right away.”
Primatene Mist HFA is intended for the temporary relief of mild symptoms of intermittent asthma (wheezing, tightness of chest, shortness of breath) in patients aged 12 years and older. It should not be considered a replacement for prescription asthma medications. It should be available in stores early next year.
After a long absence, Primatene Mist, an over-the-counter asthma inhaler removed from the market in 2011, is being reintroduced in a metered-dose inhaler with a new, environmentally friendly propellant.
But the inhaler’s comeback may prove as controversial as its removal. Respiratory medicine associations have taken issue with the Food and Drug Administration’s decision, warning patients that asthma is not a “do-it-yourself” disease that can be managed with over-the-counter medications.
The American College of Allergy, Asthma, and Immunology, American College of Chest Physicians, American Lung Association, American Thoracic Society, and the American Association of Asthma Educators have each individually protested the decision, and together sent a joint resolution to FDA decrying it. At the core of their protest are the facts that epinephrine is a symptomatic, not therapeutic, asthma treatment and that racemic epinephrine is not a not a recommended asthma treatment under the National Institutes of Health’s “Guidelines for the Diagnosis and Management of Asthma.”
CHEST has published the following statement: “The American College of Chest Physicians (CHEST) is disappointed with the FDA’s decision to approve over-the counter epinephrine (Primatene® Mist HFA) for the treatment of asthma. CHEST is a nonprofit organization dedicated to advancing best patient outcomes. Our membership of more than 19,000 members from around the world provides patient care in pulmonary, critical care, and sleep medicine.
Asthma is a serious and chronic condition with associated high health-care burden. Care for ALL patients with asthma should be under the guidance of a health-care provider. The majority of asthma patients requires treatment with a controller medication, which is only available by prescription. Frequent rescue inhaler use has been associated with increased morbidity and mortality. Over the counter availability of a reliever medication like Primatene Mist can endanger a patient’s wellbeing by providing temporary relief in symptoms, resulting in delay in seeking medical care.”
The inhaler was pulled from sales as part of an international pact to reduce ozone-depleting substances. The 1989 Montreal Protocol of Substances that Deplete the Ozone Layer and the Clean Air Act of 1990 targeted chlorofluorocarbons among those substances, and epinephrine inhalers that contained CFCs were phased out.
The new Primatene Mist HFA (Amphastar Pharmaceuticals) contains hydrofluoroalkane (HFA) propellants, which are permitted under current international and U.S. law. This puts Primatene in the same category with other inhalers, including albuterol and levalbuterol, which also use HFAs as propellants. Each dose delivers 125 mcg of epinephrine.
The inhaler itself has also been redesigned, according to Theresa Michele, MD, director of the FDA’s Division of Nonprescription Drug Products in the Center for Drug Evaluation and Research. The active ingredient is still epinephrine, albeit a smaller dose than found in the original 200-mcg mist. However, the inhaler needs to be activated before first use and cleaned every day after use to prevent a medication buildup. Like other metered-dose inhalers, it requires a priming spray before the inhalation dose, Dr. Michele noted in her online column.
“The inhaler also needs to be shaken and then sprayed once into the air before each use. It may seem strange to shake and spray the inhaler into the air each time before using it. But these two steps are critical to ensure that the medicine is properly mixed before each dose,” Dr. Michele wrote.
A public statement by FDA Commissioner Scott Gottlieb, MD, and Janet Woodcock, MD, director of the Center for Drug Evaluation and Research, asserted that the inhaler fills a clinical gap for patients with mild to moderate intermittent asthma.
“The scientific information we reviewed to approve the new version of OTC Primatene Mist shows there is a narrow population of those diagnosed with asthma that may benefit from having access to this type of OTC asthma inhaler. But the product has certain cautions. Making sure that patients can understand and apply the instructions for use was a critical consideration for the FDA. The new product is only appropriate for those with a diagnosis of mild, intermittent asthma. Patients with more severe asthma should not rely on it. Instead, they should be working with their health care provider to ensure an appropriate treatment plan for their condition.”
Before this approval, Amphastar had unsuccessfully brought the reformulated Primatene before FDA several times. The move to finally reinstate it comes after a long, and sometimes contentious, debate among patients and FDA’s Nonprescription Drugs and Pulmonary-Allergy Drugs advisory committee. A quick Internet or Facebook search brings up dozens of stories from patients who say they effectively managed their mild to moderate asthma for years with Primatene. Typically, the stories describe changing to prescription asthma medications that, for some, run into the hundreds of dollars per month. Supporters often negatively compare decades of using the inexpensive Primatene with no ill effects to their recent experiences using prescription corticosteroid inhalers.
It was 4 years ago when Amphastar first appeared before the advisory committee with the reformulated inhaler and positive safety and efficacy data. Although agreeing with the efficacy data, the advisory committee voted against approval, because some felt that asthma should always be managed by a physician; an OTC bronchodilator encouraged self-medicating and discouraged patients from seeking medical care, they said.
“On the one hand, it has been stated that a quick-relief medication available OTC is needed for use in low-income, elderly, and uninsured individuals who might otherwise not have access to treatment or be able to see a health care practitioner,” FDA documents noted. “In contrast, there is also a concern that because asthma is a potentially life-threatening condition that should be diagnosed and treated by a health care professional, availability of an OTC bronchodilator product may discourage consumers from seeking appropriate care, resulting in worse asthma outcomes.”
Two years later, the company received another blow to Primatene program. FDA’s Complete Response Letter required Amphastar to make additional changes to the packaging and run a consumer product safety study, intended to show that people could learn to use the metered-dose inhaler correctly.
In Amphastar’s 2018 first-quarter report, however, company CEO Jack Zhang, PhD, finally shared some good news. “We are pleased to announce that we have resubmitted our NDA for Primatene Mist after receiving good results from our recent human factors study. While we don’t have a Prescription Free User Drug Act [PDUFA] date yet, we plan to begin producing inventory in preparation for a launch.”
That day arrived on Nov. 8, when the PDUFA was granted. In their public letter, Dr. Gottlieb and Dr. Woodcock acknowledged the long and difficult approval path and offered reassurance that Primatene is safe and effective.
“For the right patient, our analysis of the data, including new information that was developed since this product was previously on the market, shows that there are no serious safety concerns when Primatene Mist is used as directed. The product is appropriate for mild symptoms of intermittent asthma, however, even patients with mild asthma can have severe exacerbations – so it’s still important to consult a health care provider about appropriate care and have their condition reassessed. And, of course, all patients who experience severe exacerbations should go to the emergency room right away.”
Primatene Mist HFA is intended for the temporary relief of mild symptoms of intermittent asthma (wheezing, tightness of chest, shortness of breath) in patients aged 12 years and older. It should not be considered a replacement for prescription asthma medications. It should be available in stores early next year.
Demyelinating diseases, especially MS, disrupt normal brain development in children
BERLIN – Demyelinating diseases appear to disrupt white matter development in children, slowing the trajectory of brain growth to almost unmeasurable levels, based on results from a single-center comparison study of 213 individuals.
While children with multiple sclerosis (MS) showed the most severe slowing, even a single demyelinating event slowed white matter growth, Robert A. Brown, PhD, said at the annual congress of the European Committees for Treatment and Research in Multiple Sclerosis.
Dr. Brown of the Montreal Neurological Institute at McGill University, Montreal, employed a signal mass correction of consecutive brain MRIs enhanced with magnetization transfer. Magnetization transfer ratio (MTR) quantifies myelin more effectively than does other imaging enhancement modalities, Dr. Brown said.
“It labels the macromolecules of myelin and correlates almost perfectly with Luxol fast blue stain on histology,” he said. And by measuring myelin instead of whole-brain volume, MTR sidesteps the confounders of inflammation and edema. “When tissue swells, the water dilutes the myelin. MRI is really sensitive to density, so dilution with water lowers that signal.”
But MTR isn’t failsafe either, he said, especially in teens. “A cautionary note: In healthy adolescents, white matter MTR can actually decrease, not increase, not because they are losing myelin but because the axons in brain tissue are growing so fast that they outstrip the production of new myelin. So, we can get another dilution effect here, except that instead of water, axons are diluting the myelin. We have to take that into account when using MTR.”
A volume-corrected MTR calculates both mass and volume to give what Dr. Brown termed signal mass. “We have demonstrated previously that signal mass is about twice as powerful as volume change alone for measuring the differences [in brain volume] between adults with MS and healthy controls.”
The study he presented at ECTRIMS used this technique to examine the trajectory of white matter change in a cohort of children from the Canadian Pediatric Demyelinating Disease Study who were all scanned at the same site in the same center. He compared brain volume at baseline and 1 year in 102 children with a monophasic demyelinating disease, 87 with MS, and 24 healthy, age-matched controls.
The children with MS were a median of about 17 years old at baseline, while those with a monophasic event and healthy controls were a median of about 12 years old. Median follow-up was 1 year in the healthy controls, 2 years in the MS cohort, and 4 years in the monophasic group. The investigators adjusted their comparisons for sex, since both bioavailable testosterone and androgen-receptor activity correlate with decreased MTR in young men. This doesn’t mean, though, that testosterone decreases myelination. Rather, it’s postulated that testosterone increases axonal caliber, which would decrease the number of neurons in each imaging voxel and, thus, the MTR signal (J Neurosci. 2008 Sep 17;28[38]:9519-24).
In the volume-only assessment, white matter in healthy controls increased at a rate of about 0.5% per year. White matter growth was about 0.2% per year in children with monophasic demyelination, which was significantly lower than in healthy controls.
“The MS children had no white matter growth that we could measure,” with an annual change of about 0.01%, Dr. Brown said. “It looks like a failure of normal development and was significantly lower than what we saw in the children with a demyelination event.”
MTR showed the expected age-associated decreases, which were highest among those with MS: –0.8% per year in healthy controls, –0.6% per year in those with a monophasic event, and –0.9% per year in those with MS.
The signal mass change showed the whole picture, Dr. Brown said. Signal mass declined 0.3% per year in healthy controls, 0.5% per year in the monophasic group, and 0.9% per year in the MS group – a significantly worse trajectory than either the control subjects or those with a monophasic event.
“Signal mass puts it all together and gives us the total picture of tissue loss, with quite severe loss in children with MS. It seems as though both monophasic insult and pediatric-onset MS disrupt brain development.”
Dr. Brown has been a consultant for NeuroRx Research and Biogen.
SOURCE: Brown RA et al. Mult Scler. 2018;24(S2):27-8, Abstract 63.
BERLIN – Demyelinating diseases appear to disrupt white matter development in children, slowing the trajectory of brain growth to almost unmeasurable levels, based on results from a single-center comparison study of 213 individuals.
While children with multiple sclerosis (MS) showed the most severe slowing, even a single demyelinating event slowed white matter growth, Robert A. Brown, PhD, said at the annual congress of the European Committees for Treatment and Research in Multiple Sclerosis.
Dr. Brown of the Montreal Neurological Institute at McGill University, Montreal, employed a signal mass correction of consecutive brain MRIs enhanced with magnetization transfer. Magnetization transfer ratio (MTR) quantifies myelin more effectively than does other imaging enhancement modalities, Dr. Brown said.
“It labels the macromolecules of myelin and correlates almost perfectly with Luxol fast blue stain on histology,” he said. And by measuring myelin instead of whole-brain volume, MTR sidesteps the confounders of inflammation and edema. “When tissue swells, the water dilutes the myelin. MRI is really sensitive to density, so dilution with water lowers that signal.”
But MTR isn’t failsafe either, he said, especially in teens. “A cautionary note: In healthy adolescents, white matter MTR can actually decrease, not increase, not because they are losing myelin but because the axons in brain tissue are growing so fast that they outstrip the production of new myelin. So, we can get another dilution effect here, except that instead of water, axons are diluting the myelin. We have to take that into account when using MTR.”
A volume-corrected MTR calculates both mass and volume to give what Dr. Brown termed signal mass. “We have demonstrated previously that signal mass is about twice as powerful as volume change alone for measuring the differences [in brain volume] between adults with MS and healthy controls.”
The study he presented at ECTRIMS used this technique to examine the trajectory of white matter change in a cohort of children from the Canadian Pediatric Demyelinating Disease Study who were all scanned at the same site in the same center. He compared brain volume at baseline and 1 year in 102 children with a monophasic demyelinating disease, 87 with MS, and 24 healthy, age-matched controls.
The children with MS were a median of about 17 years old at baseline, while those with a monophasic event and healthy controls were a median of about 12 years old. Median follow-up was 1 year in the healthy controls, 2 years in the MS cohort, and 4 years in the monophasic group. The investigators adjusted their comparisons for sex, since both bioavailable testosterone and androgen-receptor activity correlate with decreased MTR in young men. This doesn’t mean, though, that testosterone decreases myelination. Rather, it’s postulated that testosterone increases axonal caliber, which would decrease the number of neurons in each imaging voxel and, thus, the MTR signal (J Neurosci. 2008 Sep 17;28[38]:9519-24).
In the volume-only assessment, white matter in healthy controls increased at a rate of about 0.5% per year. White matter growth was about 0.2% per year in children with monophasic demyelination, which was significantly lower than in healthy controls.
“The MS children had no white matter growth that we could measure,” with an annual change of about 0.01%, Dr. Brown said. “It looks like a failure of normal development and was significantly lower than what we saw in the children with a demyelination event.”
MTR showed the expected age-associated decreases, which were highest among those with MS: –0.8% per year in healthy controls, –0.6% per year in those with a monophasic event, and –0.9% per year in those with MS.
The signal mass change showed the whole picture, Dr. Brown said. Signal mass declined 0.3% per year in healthy controls, 0.5% per year in the monophasic group, and 0.9% per year in the MS group – a significantly worse trajectory than either the control subjects or those with a monophasic event.
“Signal mass puts it all together and gives us the total picture of tissue loss, with quite severe loss in children with MS. It seems as though both monophasic insult and pediatric-onset MS disrupt brain development.”
Dr. Brown has been a consultant for NeuroRx Research and Biogen.
SOURCE: Brown RA et al. Mult Scler. 2018;24(S2):27-8, Abstract 63.
BERLIN – Demyelinating diseases appear to disrupt white matter development in children, slowing the trajectory of brain growth to almost unmeasurable levels, based on results from a single-center comparison study of 213 individuals.
While children with multiple sclerosis (MS) showed the most severe slowing, even a single demyelinating event slowed white matter growth, Robert A. Brown, PhD, said at the annual congress of the European Committees for Treatment and Research in Multiple Sclerosis.
Dr. Brown of the Montreal Neurological Institute at McGill University, Montreal, employed a signal mass correction of consecutive brain MRIs enhanced with magnetization transfer. Magnetization transfer ratio (MTR) quantifies myelin more effectively than does other imaging enhancement modalities, Dr. Brown said.
“It labels the macromolecules of myelin and correlates almost perfectly with Luxol fast blue stain on histology,” he said. And by measuring myelin instead of whole-brain volume, MTR sidesteps the confounders of inflammation and edema. “When tissue swells, the water dilutes the myelin. MRI is really sensitive to density, so dilution with water lowers that signal.”
But MTR isn’t failsafe either, he said, especially in teens. “A cautionary note: In healthy adolescents, white matter MTR can actually decrease, not increase, not because they are losing myelin but because the axons in brain tissue are growing so fast that they outstrip the production of new myelin. So, we can get another dilution effect here, except that instead of water, axons are diluting the myelin. We have to take that into account when using MTR.”
A volume-corrected MTR calculates both mass and volume to give what Dr. Brown termed signal mass. “We have demonstrated previously that signal mass is about twice as powerful as volume change alone for measuring the differences [in brain volume] between adults with MS and healthy controls.”
The study he presented at ECTRIMS used this technique to examine the trajectory of white matter change in a cohort of children from the Canadian Pediatric Demyelinating Disease Study who were all scanned at the same site in the same center. He compared brain volume at baseline and 1 year in 102 children with a monophasic demyelinating disease, 87 with MS, and 24 healthy, age-matched controls.
The children with MS were a median of about 17 years old at baseline, while those with a monophasic event and healthy controls were a median of about 12 years old. Median follow-up was 1 year in the healthy controls, 2 years in the MS cohort, and 4 years in the monophasic group. The investigators adjusted their comparisons for sex, since both bioavailable testosterone and androgen-receptor activity correlate with decreased MTR in young men. This doesn’t mean, though, that testosterone decreases myelination. Rather, it’s postulated that testosterone increases axonal caliber, which would decrease the number of neurons in each imaging voxel and, thus, the MTR signal (J Neurosci. 2008 Sep 17;28[38]:9519-24).
In the volume-only assessment, white matter in healthy controls increased at a rate of about 0.5% per year. White matter growth was about 0.2% per year in children with monophasic demyelination, which was significantly lower than in healthy controls.
“The MS children had no white matter growth that we could measure,” with an annual change of about 0.01%, Dr. Brown said. “It looks like a failure of normal development and was significantly lower than what we saw in the children with a demyelination event.”
MTR showed the expected age-associated decreases, which were highest among those with MS: –0.8% per year in healthy controls, –0.6% per year in those with a monophasic event, and –0.9% per year in those with MS.
The signal mass change showed the whole picture, Dr. Brown said. Signal mass declined 0.3% per year in healthy controls, 0.5% per year in the monophasic group, and 0.9% per year in the MS group – a significantly worse trajectory than either the control subjects or those with a monophasic event.
“Signal mass puts it all together and gives us the total picture of tissue loss, with quite severe loss in children with MS. It seems as though both monophasic insult and pediatric-onset MS disrupt brain development.”
Dr. Brown has been a consultant for NeuroRx Research and Biogen.
SOURCE: Brown RA et al. Mult Scler. 2018;24(S2):27-8, Abstract 63.
REPORTING FROM ECTRIMS 2018
Key clinical point: Demyelinating disorders disrupt brain growth in children.
Major finding: Children with MS had virtually no white matter growth, and those with ADM lagged significantly behind controls.
Study details: The prospective imaging study comprised 24 controls, 102 with an ADM, and 87 with MS.
Disclosures: Dr. Brown has been a consultant for NeuroRx Research and Biogen Idec.
Source: Brown RA et al. Mult Scler. 2018;24(S2):27-8, Abstract 63
More acute flaccid myelitis cases confirmed by CDC
Acute flaccid myelitis (AFM) has stricken 90 patients in the United States this year and another 252 cases are being investigated, according to new data from the Centers for Disease Control and Prevention.
The number of confirmed cases is triple that seen in 2017.
Nearly all of the patients (90%) were children aged 2-8 years, and 99% experienced a fever and /or respiratory illness 7-10 days before the onset of symptoms. But although the prodrome and seasonality of AFM suggest an infective process, only 54% of the patients tested positive for the virus, Nancy Messonnier, MD, said during a briefing held by CDC officials. The most common findings were the enteroviruses EV-A71 (29%) and EV-D68 (37%); other viruses were recovered in the remaining pathogen-positive cases.
It’s not at all clear that these were causative agents, said Dr. Messonnier, director of the National Center for Immunization and Respiratory Diseases.
“At this time of year lots of children have a fever and respiratory infections,” she said. AFM may be caused by one of the identified viruses, a still-undetected pathogen, or a pathogen hiding in untested tissue. “Or, it could be an infection that’s kicking off an immune process,” attacking gray matter in the spinal cord.
The reported increase in cases must be viewed cautiously, Dr. Messonnier said. Physicians are becoming more aware of AFM, so the spike could represent an increase in reporting as well as actual incidence.
It’s not clear why the disease manifests almost exclusively in children, Dr. Messonnier said. Nor do health officials have much of a grasp on AFM’s long-term sequelae.
“We know that patients can recover fully, but at least half don’t, and some of those have serious sequelae. Unfortunately, we have not been following every patient, so this is a gap in our knowledge.”
A newly created national task force will examine AFM’s long-term effects, Dr. Messonnier said. The task force will also look at mortality; health departments across the country will examine mortality records to identify any past deaths preceded by AFM-like symptoms.
“One of the reasons we have convened this task force is to think about this hypothesis [of an autoimmune syndrome]. We have not backed off on the idea of an infectious organism causing it, but we are thinking more broadly,” Dr. Messonnier said.
Some anti-immunization groups are blaming vaccines for the disease, noting that several childhood vaccines list encephalomyelitis and transverse myelitis as possible adverse events.
“We are investigating every one of the cases in this and prior years and have a list of hypotheses based on the epidemiology,” Dr. Messonnier said. “I would say toxins are low on that list. Many of the children may have been vaccinated [before developing AFM] and that is something we will look at, but for now we recommend that all children should be vaccinated” according to the recommended schedule.
Additional details were published on 80 of the cases. Patients’ mean age was 4 years; 59% were male. Symptoms suggesting a viral illness occurred in 99%; these included fever (81%), cough, rhinorrhea, and congestion (78%), and vomiting and diarrhea (38%).
AFM symptoms varied; 47% had only upper limb involvement, 9% only lower limb, 15% two or three upper, and 29% all four limbs. All the patients with confirmed AFM were hospitalized, and 59% treated in intensive care units. There were no deaths (MMWR. 2018;ePub:13 November. DOI: http://dx.doi.org/10.15585/mmwr.mm6745e1).
AFM remains extremely rare, Dr. Messonnier said. But physicians should be alert for any signs of sudden limb weakness in children and report those immediately. The workup should include questions about recent fever with or without respiratory or gastrointestinal symptoms. Prompt collection of viral testing samples (cerebrospinal fluid, serum, respiratory, and stool specimens) is critical.
Additional information for health care professionals is available on the CDC AFM web page.
Acute flaccid myelitis (AFM) has stricken 90 patients in the United States this year and another 252 cases are being investigated, according to new data from the Centers for Disease Control and Prevention.
The number of confirmed cases is triple that seen in 2017.
Nearly all of the patients (90%) were children aged 2-8 years, and 99% experienced a fever and /or respiratory illness 7-10 days before the onset of symptoms. But although the prodrome and seasonality of AFM suggest an infective process, only 54% of the patients tested positive for the virus, Nancy Messonnier, MD, said during a briefing held by CDC officials. The most common findings were the enteroviruses EV-A71 (29%) and EV-D68 (37%); other viruses were recovered in the remaining pathogen-positive cases.
It’s not at all clear that these were causative agents, said Dr. Messonnier, director of the National Center for Immunization and Respiratory Diseases.
“At this time of year lots of children have a fever and respiratory infections,” she said. AFM may be caused by one of the identified viruses, a still-undetected pathogen, or a pathogen hiding in untested tissue. “Or, it could be an infection that’s kicking off an immune process,” attacking gray matter in the spinal cord.
The reported increase in cases must be viewed cautiously, Dr. Messonnier said. Physicians are becoming more aware of AFM, so the spike could represent an increase in reporting as well as actual incidence.
It’s not clear why the disease manifests almost exclusively in children, Dr. Messonnier said. Nor do health officials have much of a grasp on AFM’s long-term sequelae.
“We know that patients can recover fully, but at least half don’t, and some of those have serious sequelae. Unfortunately, we have not been following every patient, so this is a gap in our knowledge.”
A newly created national task force will examine AFM’s long-term effects, Dr. Messonnier said. The task force will also look at mortality; health departments across the country will examine mortality records to identify any past deaths preceded by AFM-like symptoms.
“One of the reasons we have convened this task force is to think about this hypothesis [of an autoimmune syndrome]. We have not backed off on the idea of an infectious organism causing it, but we are thinking more broadly,” Dr. Messonnier said.
Some anti-immunization groups are blaming vaccines for the disease, noting that several childhood vaccines list encephalomyelitis and transverse myelitis as possible adverse events.
“We are investigating every one of the cases in this and prior years and have a list of hypotheses based on the epidemiology,” Dr. Messonnier said. “I would say toxins are low on that list. Many of the children may have been vaccinated [before developing AFM] and that is something we will look at, but for now we recommend that all children should be vaccinated” according to the recommended schedule.
Additional details were published on 80 of the cases. Patients’ mean age was 4 years; 59% were male. Symptoms suggesting a viral illness occurred in 99%; these included fever (81%), cough, rhinorrhea, and congestion (78%), and vomiting and diarrhea (38%).
AFM symptoms varied; 47% had only upper limb involvement, 9% only lower limb, 15% two or three upper, and 29% all four limbs. All the patients with confirmed AFM were hospitalized, and 59% treated in intensive care units. There were no deaths (MMWR. 2018;ePub:13 November. DOI: http://dx.doi.org/10.15585/mmwr.mm6745e1).
AFM remains extremely rare, Dr. Messonnier said. But physicians should be alert for any signs of sudden limb weakness in children and report those immediately. The workup should include questions about recent fever with or without respiratory or gastrointestinal symptoms. Prompt collection of viral testing samples (cerebrospinal fluid, serum, respiratory, and stool specimens) is critical.
Additional information for health care professionals is available on the CDC AFM web page.
Acute flaccid myelitis (AFM) has stricken 90 patients in the United States this year and another 252 cases are being investigated, according to new data from the Centers for Disease Control and Prevention.
The number of confirmed cases is triple that seen in 2017.
Nearly all of the patients (90%) were children aged 2-8 years, and 99% experienced a fever and /or respiratory illness 7-10 days before the onset of symptoms. But although the prodrome and seasonality of AFM suggest an infective process, only 54% of the patients tested positive for the virus, Nancy Messonnier, MD, said during a briefing held by CDC officials. The most common findings were the enteroviruses EV-A71 (29%) and EV-D68 (37%); other viruses were recovered in the remaining pathogen-positive cases.
It’s not at all clear that these were causative agents, said Dr. Messonnier, director of the National Center for Immunization and Respiratory Diseases.
“At this time of year lots of children have a fever and respiratory infections,” she said. AFM may be caused by one of the identified viruses, a still-undetected pathogen, or a pathogen hiding in untested tissue. “Or, it could be an infection that’s kicking off an immune process,” attacking gray matter in the spinal cord.
The reported increase in cases must be viewed cautiously, Dr. Messonnier said. Physicians are becoming more aware of AFM, so the spike could represent an increase in reporting as well as actual incidence.
It’s not clear why the disease manifests almost exclusively in children, Dr. Messonnier said. Nor do health officials have much of a grasp on AFM’s long-term sequelae.
“We know that patients can recover fully, but at least half don’t, and some of those have serious sequelae. Unfortunately, we have not been following every patient, so this is a gap in our knowledge.”
A newly created national task force will examine AFM’s long-term effects, Dr. Messonnier said. The task force will also look at mortality; health departments across the country will examine mortality records to identify any past deaths preceded by AFM-like symptoms.
“One of the reasons we have convened this task force is to think about this hypothesis [of an autoimmune syndrome]. We have not backed off on the idea of an infectious organism causing it, but we are thinking more broadly,” Dr. Messonnier said.
Some anti-immunization groups are blaming vaccines for the disease, noting that several childhood vaccines list encephalomyelitis and transverse myelitis as possible adverse events.
“We are investigating every one of the cases in this and prior years and have a list of hypotheses based on the epidemiology,” Dr. Messonnier said. “I would say toxins are low on that list. Many of the children may have been vaccinated [before developing AFM] and that is something we will look at, but for now we recommend that all children should be vaccinated” according to the recommended schedule.
Additional details were published on 80 of the cases. Patients’ mean age was 4 years; 59% were male. Symptoms suggesting a viral illness occurred in 99%; these included fever (81%), cough, rhinorrhea, and congestion (78%), and vomiting and diarrhea (38%).
AFM symptoms varied; 47% had only upper limb involvement, 9% only lower limb, 15% two or three upper, and 29% all four limbs. All the patients with confirmed AFM were hospitalized, and 59% treated in intensive care units. There were no deaths (MMWR. 2018;ePub:13 November. DOI: http://dx.doi.org/10.15585/mmwr.mm6745e1).
AFM remains extremely rare, Dr. Messonnier said. But physicians should be alert for any signs of sudden limb weakness in children and report those immediately. The workup should include questions about recent fever with or without respiratory or gastrointestinal symptoms. Prompt collection of viral testing samples (cerebrospinal fluid, serum, respiratory, and stool specimens) is critical.
Additional information for health care professionals is available on the CDC AFM web page.
FROM A CDC BRIEFING
Delay in plasma exchange increases chance of poor outcomes in NMOSD
BERLIN – A delay in undertaking plasma exchange may predict a poorer outcome after a first attack of neuromyelitis optica spectrum disorder, while antibodies to myelin oligodendrocyte glycoprotein (MOG) appear to predict a more positive outcome.
“We saw that for each day of delay in plasma exchange, the Expanded Disability Status Scale [EDSS] at 6 months increased by about 0.028 points, indicating a worse prognosis,” Maxime Guillaume, MD, said at the annual congress of the European Committee for Treatment and Research in Multiples Sclerosis.
However, said Dr. Guillaume, a resident at Rouen University Hospital, France, steroids are still a reasonable first-line therapy as long as they are discontinued quickly if they don’t appear to be helping. Plasma exchange is most effective if administered less than 2 weeks after symptom onset.
His study examined 6-month outcomes among 214 attacks in 188 patients; some patients had several first attacks in different areas. Response was defined in two ways. First, patients were clinically classified as having a good response, a bad response, or no response to treatment. The second definition was based on the EDSS. Good response was an EDSS decrease of at least 2 points for an initial score of 3 or higher, or a decrease of 1 point if the initial score was less than 3. Poor response was an EDSS that decreased without reaching these thresholds.
The cohort was largely female, with a mean age of 38 years. Most (55%) were positive for antibodies against aquaporin-4. Anti-MOG antibodies were present in 30%. A total of 7.5% were negative for both antibodies, and the remainder had an undetermined serotype.
The clinical presentations varied. Most frequently, patients presented with myelitis only (44%). This was followed by optic neuritis only (34%), both myelitis and optic neuritis (8%), and myelitis plus brainstem involvement (5%). Other clinical manifestations were acute demyelinating encephalomyelitis, and encephalitis alone.
The most common treatment was methylprednisolone (73%), followed by plasma exchange (25%), which occurred at a median of 9 days after symptom onset.
Outcomes varied according to the definition of response. By clinical characteristics, there was a complete response in 41, a partial response in 122, and no response in 51. By change in EDSS, 136 had a good response and 27 a partial response; 51 were still considered nonresponders.
Dr. Guillaume conducted a multivariate analysis to determine predictive factors. In both definitions, anti-MOG antibodies nearly quadrupled the chance of a good treatment response, and delaying plasma exchange was associated with a significantly increased chance of a poor response. When judged by the clinical response definition, multiple lines of treatment also were associated with a poor response. This, he said, was another reflection of plasma exchange delay.
Dr. Guillaume had no financial disclosures.
BERLIN – A delay in undertaking plasma exchange may predict a poorer outcome after a first attack of neuromyelitis optica spectrum disorder, while antibodies to myelin oligodendrocyte glycoprotein (MOG) appear to predict a more positive outcome.
“We saw that for each day of delay in plasma exchange, the Expanded Disability Status Scale [EDSS] at 6 months increased by about 0.028 points, indicating a worse prognosis,” Maxime Guillaume, MD, said at the annual congress of the European Committee for Treatment and Research in Multiples Sclerosis.
However, said Dr. Guillaume, a resident at Rouen University Hospital, France, steroids are still a reasonable first-line therapy as long as they are discontinued quickly if they don’t appear to be helping. Plasma exchange is most effective if administered less than 2 weeks after symptom onset.
His study examined 6-month outcomes among 214 attacks in 188 patients; some patients had several first attacks in different areas. Response was defined in two ways. First, patients were clinically classified as having a good response, a bad response, or no response to treatment. The second definition was based on the EDSS. Good response was an EDSS decrease of at least 2 points for an initial score of 3 or higher, or a decrease of 1 point if the initial score was less than 3. Poor response was an EDSS that decreased without reaching these thresholds.
The cohort was largely female, with a mean age of 38 years. Most (55%) were positive for antibodies against aquaporin-4. Anti-MOG antibodies were present in 30%. A total of 7.5% were negative for both antibodies, and the remainder had an undetermined serotype.
The clinical presentations varied. Most frequently, patients presented with myelitis only (44%). This was followed by optic neuritis only (34%), both myelitis and optic neuritis (8%), and myelitis plus brainstem involvement (5%). Other clinical manifestations were acute demyelinating encephalomyelitis, and encephalitis alone.
The most common treatment was methylprednisolone (73%), followed by plasma exchange (25%), which occurred at a median of 9 days after symptom onset.
Outcomes varied according to the definition of response. By clinical characteristics, there was a complete response in 41, a partial response in 122, and no response in 51. By change in EDSS, 136 had a good response and 27 a partial response; 51 were still considered nonresponders.
Dr. Guillaume conducted a multivariate analysis to determine predictive factors. In both definitions, anti-MOG antibodies nearly quadrupled the chance of a good treatment response, and delaying plasma exchange was associated with a significantly increased chance of a poor response. When judged by the clinical response definition, multiple lines of treatment also were associated with a poor response. This, he said, was another reflection of plasma exchange delay.
Dr. Guillaume had no financial disclosures.
BERLIN – A delay in undertaking plasma exchange may predict a poorer outcome after a first attack of neuromyelitis optica spectrum disorder, while antibodies to myelin oligodendrocyte glycoprotein (MOG) appear to predict a more positive outcome.
“We saw that for each day of delay in plasma exchange, the Expanded Disability Status Scale [EDSS] at 6 months increased by about 0.028 points, indicating a worse prognosis,” Maxime Guillaume, MD, said at the annual congress of the European Committee for Treatment and Research in Multiples Sclerosis.
However, said Dr. Guillaume, a resident at Rouen University Hospital, France, steroids are still a reasonable first-line therapy as long as they are discontinued quickly if they don’t appear to be helping. Plasma exchange is most effective if administered less than 2 weeks after symptom onset.
His study examined 6-month outcomes among 214 attacks in 188 patients; some patients had several first attacks in different areas. Response was defined in two ways. First, patients were clinically classified as having a good response, a bad response, or no response to treatment. The second definition was based on the EDSS. Good response was an EDSS decrease of at least 2 points for an initial score of 3 or higher, or a decrease of 1 point if the initial score was less than 3. Poor response was an EDSS that decreased without reaching these thresholds.
The cohort was largely female, with a mean age of 38 years. Most (55%) were positive for antibodies against aquaporin-4. Anti-MOG antibodies were present in 30%. A total of 7.5% were negative for both antibodies, and the remainder had an undetermined serotype.
The clinical presentations varied. Most frequently, patients presented with myelitis only (44%). This was followed by optic neuritis only (34%), both myelitis and optic neuritis (8%), and myelitis plus brainstem involvement (5%). Other clinical manifestations were acute demyelinating encephalomyelitis, and encephalitis alone.
The most common treatment was methylprednisolone (73%), followed by plasma exchange (25%), which occurred at a median of 9 days after symptom onset.
Outcomes varied according to the definition of response. By clinical characteristics, there was a complete response in 41, a partial response in 122, and no response in 51. By change in EDSS, 136 had a good response and 27 a partial response; 51 were still considered nonresponders.
Dr. Guillaume conducted a multivariate analysis to determine predictive factors. In both definitions, anti-MOG antibodies nearly quadrupled the chance of a good treatment response, and delaying plasma exchange was associated with a significantly increased chance of a poor response. When judged by the clinical response definition, multiple lines of treatment also were associated with a poor response. This, he said, was another reflection of plasma exchange delay.
Dr. Guillaume had no financial disclosures.
REPORTING FROM ECTRIMS 2018
Key clinical point:
Major finding: Each day’s delay in receiving plasma exchange increased the mean 6-month EDSS by about 0.028 points.
Study details: The retrospective study comprised 214 attacks in 188 patients.
Disclosures: Dr. Guillaume had no financial disclosures.
Source: Guillaume M. et al. ECTRIMS 2018, Abstract 211.
BAN2401 subanalyses attempt to ease concerns over study design and findings
BARCELONA – Alzheimer’s disease genetic risk status didn’t influence positive findings of the investigational monoclonal antibody, BAN2401, in a post hoc analysis of a phase 2 study’s secondary endpoint, Eisai said in a report released during the Clinical Trials on Alzheimer’s Disease conference.
In fact, according to the new analysis, the positive data presented last summer probably underestimated the molecule’s benefit to homozygous carriers of the apolipoprotein E epsilon-4 (APOE4), Chad Swanson, PhD, said at the meeting.
The new data cut was based on a small fraction of the 856 patients with early Alzheimer’s disease (AD) who were enrolled in Study 201: 10 APOE4 carriers and 69 noncarriers who completed 18 months on infusions of BAN2401 at 10 mg/kg biweekly, the only beneficial dose. The subanalysis determined that carriers benefited much more than did noncarriers on the three clinical measures, said Dr. Swanson, senior director of neurology clinical research at Eisai, and the study’s director:
- The Alzheimer’s Disease Composite Score (ADCOMS), a new measure of subtle cognitive changes in early disease: Carriers, 63% less decline than placebo vs. 7% less in noncarriers.
- Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-Cog): Carriers, 84% less decline than placebo vs. 43% less in noncarriers.
- Clinical Dementia Rating-Sum of Boxes (CDR-SB): Carriers, 60% less decline than placebo vs. a 7% worsening in noncarriers.
To strengthen the power of the analysis, Dr. Swanson pooled data from the entire 18 months of both the 10 mg/kg biweekly and the next-highest dose (10 mg/kg monthly). This increased the numbers to 273 carriers and 141 noncarriers who had at least one exposure to the antibody.
He said this corrected the APOE4 imbalance and showed a 25% slowing of ADCOMS decline in carriers, a 6% slowing in noncarriers, and a 21% slowing overall, relative to placebo.
The somewhat counterintuitive findings took even copresenter Jeffrey L. Cummings, MD, by surprise.
“I would have hypothesized a greater effect in noncarriers than carriers, but that’s the great thing about data – they challenge our assumptions,” said Dr. Cummings, director of the Center for Neurodegeneration and Translational Neuroscience and director emeritus of the Cleveland Clinic Lou Ruvo Center for Brain Health in Las Vegas and a consultant for both Eisai and Biogen, the company’s BAN2401 developmental partner. He postulated that APOE4-driven differences in plaque composition could have contributed to the observed benefit. “I think this also points to a very interesting biology that we don’t yet know. The plaque compactness is different, the distribution of diffuse plaques is different. This will bear a lot of additional analysis.”
Study 201 randomized patients with early Alzheimer’s to up to 18 months of treatment with placebo or infusions of BAN2401 at 2.5 mg/kg biweekly, 5 mg/kg monthly, 5 mg/kg biweekly, 10 mg/kg monthly, or 10 mg/kg biweekly. It had two unusual design features. First, patents were allocated to treatment arms by a Bayesian algorithm. The computer program examined results after every 50 enrollees and then allocated new subjects to what were, at that point, the most effective two doses. Additionally, the 18-month study was designed with a potential 12-month exit point, if computer modeling showed that it had at least an 80% probability of reaching at least a 25% cognitive benefit. In December, Eisai announced that the study hit just a 64% probability, missing the primary endpoint. But because Eisai felt the numbers were moving in the right direction, it continued with the additional 6 months of treatment, as allowed for in the study design, and then reanalyzed results with conventional statistics.
Thus, the successes reported at the Alzheimer’s Association International Conference in July and reanalyzed at CTAD, were secondary cognitive and functional outcomes.
Partway through the trial, a European regulatory body became alarmed at the rate of amyloid-related imaging abnormalities (ARIA) in the APOE4 carriers and excluded them from the highest-dose group. This meant that carriers comprised about 70%-80% of every unsuccessful treatment arm but just 29% of the successful one. The unbalanced randomization caused July’s skepticism. The CTAD subanalysis didn’t entirely alleviate it, and several acclaimed Alzheimer’s researchers gave it voice.
“You showed no difference in placebo rates of decline, but an increased benefit in the E4 carriers, which was really interesting,” said Reisa Sperling, MD, of Brigham and Women’s Hospital, Boston. “One difference in the E4 carriers was their rate of ARIA and how long they stayed in the study. How did you account for these issues in this analysis?”
“We didn’t specifically look at that kind of question,” Dr. Swanson said. “I think we feel that we actually see effects in both carriers and noncarriers, and we are still exploring the data and will keep looking through them to see what we can find.”
Gil Rabinovici, MD, also expressed some reservations.
“I agree that the post hoc analyses are encouraging, but I wouldn’t say they alleviate the concern when you have such a dramatic imbalance in a core feature of this disease, like APOE4 between the placebo and the high-dose group,” said Dr. Rabinovici, the Edward Fein and Pearl Landrith Endowed Professor in Memory & Aging at the University of California, San Francisco. “The people on this panel know far more than I do of the pitfalls of these kinds of analyses. We really need to see true randomization to put this issue to rest.”
Biomarkers support subanalysis finding
Dr. Swanson also presented new cerebrospinal fluid biomarker data showing changes in phosphorylated tau, neurogranin, and neurofilament light chain that support the overall 47% slowing of cognitive decline reported last summer. The 10 mg/kg biweekly and monthly groups were again combined to increase the sample size, but it remained quite small, with full data on 16 in the placebo group and 23 in the active group:
- Neurogranin, a synaptic protein that is a marker of neuronal damage, decreased by a median 58 pg/mL (11%), compared with a 13.5-pg/mL increase in the placebo group.
- Phosphorylated tau, a marker of tau pathology in the brain, decreased by a median 12 pg/mL (13%), compared with no change in the placebo group.
- Neurofilament light chain, a neuronal structural scaffold protein that is a marker of axonal degeneration, increased by a median 75 pg/mL in the active group, compared with a 156-pg/mL increase in the placebo group – a 48% difference.
The positive biomarker data bolstered the subanalysis to some extent, researchers felt. But in the end, Study 201 is just a first step for BAN2401, said Laurie Ryan, PhD, chief of the dementias of aging branch in the division of neuroscience at the National Institute on Aging.
“Today’s presentation gave us a new look at the trial data from the summer,” Dr. Ryan said in an interview. “The new analysis supports the findings previously released but is still preliminary. Nothing is definitive in a phase 2 study, so while it appears to suggest a potential positive, beneficial result, it needs further testing.”
Eisai has made its subanalysis presentation slides publicly available.
Dr. Swanson is an employee of Eisai. Dr. Cummings is a consultant for Eisai and Biogen. Dr. Sperling has consulted for numerous pharmaceutical companies. Dr. Rabinovici and Dr. Ryan have no disclosures.
SOURCE: Swanson C et al. CTAD, Symposium 3.
BARCELONA – Alzheimer’s disease genetic risk status didn’t influence positive findings of the investigational monoclonal antibody, BAN2401, in a post hoc analysis of a phase 2 study’s secondary endpoint, Eisai said in a report released during the Clinical Trials on Alzheimer’s Disease conference.
In fact, according to the new analysis, the positive data presented last summer probably underestimated the molecule’s benefit to homozygous carriers of the apolipoprotein E epsilon-4 (APOE4), Chad Swanson, PhD, said at the meeting.
The new data cut was based on a small fraction of the 856 patients with early Alzheimer’s disease (AD) who were enrolled in Study 201: 10 APOE4 carriers and 69 noncarriers who completed 18 months on infusions of BAN2401 at 10 mg/kg biweekly, the only beneficial dose. The subanalysis determined that carriers benefited much more than did noncarriers on the three clinical measures, said Dr. Swanson, senior director of neurology clinical research at Eisai, and the study’s director:
- The Alzheimer’s Disease Composite Score (ADCOMS), a new measure of subtle cognitive changes in early disease: Carriers, 63% less decline than placebo vs. 7% less in noncarriers.
- Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-Cog): Carriers, 84% less decline than placebo vs. 43% less in noncarriers.
- Clinical Dementia Rating-Sum of Boxes (CDR-SB): Carriers, 60% less decline than placebo vs. a 7% worsening in noncarriers.
To strengthen the power of the analysis, Dr. Swanson pooled data from the entire 18 months of both the 10 mg/kg biweekly and the next-highest dose (10 mg/kg monthly). This increased the numbers to 273 carriers and 141 noncarriers who had at least one exposure to the antibody.
He said this corrected the APOE4 imbalance and showed a 25% slowing of ADCOMS decline in carriers, a 6% slowing in noncarriers, and a 21% slowing overall, relative to placebo.
The somewhat counterintuitive findings took even copresenter Jeffrey L. Cummings, MD, by surprise.
“I would have hypothesized a greater effect in noncarriers than carriers, but that’s the great thing about data – they challenge our assumptions,” said Dr. Cummings, director of the Center for Neurodegeneration and Translational Neuroscience and director emeritus of the Cleveland Clinic Lou Ruvo Center for Brain Health in Las Vegas and a consultant for both Eisai and Biogen, the company’s BAN2401 developmental partner. He postulated that APOE4-driven differences in plaque composition could have contributed to the observed benefit. “I think this also points to a very interesting biology that we don’t yet know. The plaque compactness is different, the distribution of diffuse plaques is different. This will bear a lot of additional analysis.”
Study 201 randomized patients with early Alzheimer’s to up to 18 months of treatment with placebo or infusions of BAN2401 at 2.5 mg/kg biweekly, 5 mg/kg monthly, 5 mg/kg biweekly, 10 mg/kg monthly, or 10 mg/kg biweekly. It had two unusual design features. First, patents were allocated to treatment arms by a Bayesian algorithm. The computer program examined results after every 50 enrollees and then allocated new subjects to what were, at that point, the most effective two doses. Additionally, the 18-month study was designed with a potential 12-month exit point, if computer modeling showed that it had at least an 80% probability of reaching at least a 25% cognitive benefit. In December, Eisai announced that the study hit just a 64% probability, missing the primary endpoint. But because Eisai felt the numbers were moving in the right direction, it continued with the additional 6 months of treatment, as allowed for in the study design, and then reanalyzed results with conventional statistics.
Thus, the successes reported at the Alzheimer’s Association International Conference in July and reanalyzed at CTAD, were secondary cognitive and functional outcomes.
Partway through the trial, a European regulatory body became alarmed at the rate of amyloid-related imaging abnormalities (ARIA) in the APOE4 carriers and excluded them from the highest-dose group. This meant that carriers comprised about 70%-80% of every unsuccessful treatment arm but just 29% of the successful one. The unbalanced randomization caused July’s skepticism. The CTAD subanalysis didn’t entirely alleviate it, and several acclaimed Alzheimer’s researchers gave it voice.
“You showed no difference in placebo rates of decline, but an increased benefit in the E4 carriers, which was really interesting,” said Reisa Sperling, MD, of Brigham and Women’s Hospital, Boston. “One difference in the E4 carriers was their rate of ARIA and how long they stayed in the study. How did you account for these issues in this analysis?”
“We didn’t specifically look at that kind of question,” Dr. Swanson said. “I think we feel that we actually see effects in both carriers and noncarriers, and we are still exploring the data and will keep looking through them to see what we can find.”
Gil Rabinovici, MD, also expressed some reservations.
“I agree that the post hoc analyses are encouraging, but I wouldn’t say they alleviate the concern when you have such a dramatic imbalance in a core feature of this disease, like APOE4 between the placebo and the high-dose group,” said Dr. Rabinovici, the Edward Fein and Pearl Landrith Endowed Professor in Memory & Aging at the University of California, San Francisco. “The people on this panel know far more than I do of the pitfalls of these kinds of analyses. We really need to see true randomization to put this issue to rest.”
Biomarkers support subanalysis finding
Dr. Swanson also presented new cerebrospinal fluid biomarker data showing changes in phosphorylated tau, neurogranin, and neurofilament light chain that support the overall 47% slowing of cognitive decline reported last summer. The 10 mg/kg biweekly and monthly groups were again combined to increase the sample size, but it remained quite small, with full data on 16 in the placebo group and 23 in the active group:
- Neurogranin, a synaptic protein that is a marker of neuronal damage, decreased by a median 58 pg/mL (11%), compared with a 13.5-pg/mL increase in the placebo group.
- Phosphorylated tau, a marker of tau pathology in the brain, decreased by a median 12 pg/mL (13%), compared with no change in the placebo group.
- Neurofilament light chain, a neuronal structural scaffold protein that is a marker of axonal degeneration, increased by a median 75 pg/mL in the active group, compared with a 156-pg/mL increase in the placebo group – a 48% difference.
The positive biomarker data bolstered the subanalysis to some extent, researchers felt. But in the end, Study 201 is just a first step for BAN2401, said Laurie Ryan, PhD, chief of the dementias of aging branch in the division of neuroscience at the National Institute on Aging.
“Today’s presentation gave us a new look at the trial data from the summer,” Dr. Ryan said in an interview. “The new analysis supports the findings previously released but is still preliminary. Nothing is definitive in a phase 2 study, so while it appears to suggest a potential positive, beneficial result, it needs further testing.”
Eisai has made its subanalysis presentation slides publicly available.
Dr. Swanson is an employee of Eisai. Dr. Cummings is a consultant for Eisai and Biogen. Dr. Sperling has consulted for numerous pharmaceutical companies. Dr. Rabinovici and Dr. Ryan have no disclosures.
SOURCE: Swanson C et al. CTAD, Symposium 3.
BARCELONA – Alzheimer’s disease genetic risk status didn’t influence positive findings of the investigational monoclonal antibody, BAN2401, in a post hoc analysis of a phase 2 study’s secondary endpoint, Eisai said in a report released during the Clinical Trials on Alzheimer’s Disease conference.
In fact, according to the new analysis, the positive data presented last summer probably underestimated the molecule’s benefit to homozygous carriers of the apolipoprotein E epsilon-4 (APOE4), Chad Swanson, PhD, said at the meeting.
The new data cut was based on a small fraction of the 856 patients with early Alzheimer’s disease (AD) who were enrolled in Study 201: 10 APOE4 carriers and 69 noncarriers who completed 18 months on infusions of BAN2401 at 10 mg/kg biweekly, the only beneficial dose. The subanalysis determined that carriers benefited much more than did noncarriers on the three clinical measures, said Dr. Swanson, senior director of neurology clinical research at Eisai, and the study’s director:
- The Alzheimer’s Disease Composite Score (ADCOMS), a new measure of subtle cognitive changes in early disease: Carriers, 63% less decline than placebo vs. 7% less in noncarriers.
- Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-Cog): Carriers, 84% less decline than placebo vs. 43% less in noncarriers.
- Clinical Dementia Rating-Sum of Boxes (CDR-SB): Carriers, 60% less decline than placebo vs. a 7% worsening in noncarriers.
To strengthen the power of the analysis, Dr. Swanson pooled data from the entire 18 months of both the 10 mg/kg biweekly and the next-highest dose (10 mg/kg monthly). This increased the numbers to 273 carriers and 141 noncarriers who had at least one exposure to the antibody.
He said this corrected the APOE4 imbalance and showed a 25% slowing of ADCOMS decline in carriers, a 6% slowing in noncarriers, and a 21% slowing overall, relative to placebo.
The somewhat counterintuitive findings took even copresenter Jeffrey L. Cummings, MD, by surprise.
“I would have hypothesized a greater effect in noncarriers than carriers, but that’s the great thing about data – they challenge our assumptions,” said Dr. Cummings, director of the Center for Neurodegeneration and Translational Neuroscience and director emeritus of the Cleveland Clinic Lou Ruvo Center for Brain Health in Las Vegas and a consultant for both Eisai and Biogen, the company’s BAN2401 developmental partner. He postulated that APOE4-driven differences in plaque composition could have contributed to the observed benefit. “I think this also points to a very interesting biology that we don’t yet know. The plaque compactness is different, the distribution of diffuse plaques is different. This will bear a lot of additional analysis.”
Study 201 randomized patients with early Alzheimer’s to up to 18 months of treatment with placebo or infusions of BAN2401 at 2.5 mg/kg biweekly, 5 mg/kg monthly, 5 mg/kg biweekly, 10 mg/kg monthly, or 10 mg/kg biweekly. It had two unusual design features. First, patents were allocated to treatment arms by a Bayesian algorithm. The computer program examined results after every 50 enrollees and then allocated new subjects to what were, at that point, the most effective two doses. Additionally, the 18-month study was designed with a potential 12-month exit point, if computer modeling showed that it had at least an 80% probability of reaching at least a 25% cognitive benefit. In December, Eisai announced that the study hit just a 64% probability, missing the primary endpoint. But because Eisai felt the numbers were moving in the right direction, it continued with the additional 6 months of treatment, as allowed for in the study design, and then reanalyzed results with conventional statistics.
Thus, the successes reported at the Alzheimer’s Association International Conference in July and reanalyzed at CTAD, were secondary cognitive and functional outcomes.
Partway through the trial, a European regulatory body became alarmed at the rate of amyloid-related imaging abnormalities (ARIA) in the APOE4 carriers and excluded them from the highest-dose group. This meant that carriers comprised about 70%-80% of every unsuccessful treatment arm but just 29% of the successful one. The unbalanced randomization caused July’s skepticism. The CTAD subanalysis didn’t entirely alleviate it, and several acclaimed Alzheimer’s researchers gave it voice.
“You showed no difference in placebo rates of decline, but an increased benefit in the E4 carriers, which was really interesting,” said Reisa Sperling, MD, of Brigham and Women’s Hospital, Boston. “One difference in the E4 carriers was their rate of ARIA and how long they stayed in the study. How did you account for these issues in this analysis?”
“We didn’t specifically look at that kind of question,” Dr. Swanson said. “I think we feel that we actually see effects in both carriers and noncarriers, and we are still exploring the data and will keep looking through them to see what we can find.”
Gil Rabinovici, MD, also expressed some reservations.
“I agree that the post hoc analyses are encouraging, but I wouldn’t say they alleviate the concern when you have such a dramatic imbalance in a core feature of this disease, like APOE4 between the placebo and the high-dose group,” said Dr. Rabinovici, the Edward Fein and Pearl Landrith Endowed Professor in Memory & Aging at the University of California, San Francisco. “The people on this panel know far more than I do of the pitfalls of these kinds of analyses. We really need to see true randomization to put this issue to rest.”
Biomarkers support subanalysis finding
Dr. Swanson also presented new cerebrospinal fluid biomarker data showing changes in phosphorylated tau, neurogranin, and neurofilament light chain that support the overall 47% slowing of cognitive decline reported last summer. The 10 mg/kg biweekly and monthly groups were again combined to increase the sample size, but it remained quite small, with full data on 16 in the placebo group and 23 in the active group:
- Neurogranin, a synaptic protein that is a marker of neuronal damage, decreased by a median 58 pg/mL (11%), compared with a 13.5-pg/mL increase in the placebo group.
- Phosphorylated tau, a marker of tau pathology in the brain, decreased by a median 12 pg/mL (13%), compared with no change in the placebo group.
- Neurofilament light chain, a neuronal structural scaffold protein that is a marker of axonal degeneration, increased by a median 75 pg/mL in the active group, compared with a 156-pg/mL increase in the placebo group – a 48% difference.
The positive biomarker data bolstered the subanalysis to some extent, researchers felt. But in the end, Study 201 is just a first step for BAN2401, said Laurie Ryan, PhD, chief of the dementias of aging branch in the division of neuroscience at the National Institute on Aging.
“Today’s presentation gave us a new look at the trial data from the summer,” Dr. Ryan said in an interview. “The new analysis supports the findings previously released but is still preliminary. Nothing is definitive in a phase 2 study, so while it appears to suggest a potential positive, beneficial result, it needs further testing.”
Eisai has made its subanalysis presentation slides publicly available.
Dr. Swanson is an employee of Eisai. Dr. Cummings is a consultant for Eisai and Biogen. Dr. Sperling has consulted for numerous pharmaceutical companies. Dr. Rabinovici and Dr. Ryan have no disclosures.
SOURCE: Swanson C et al. CTAD, Symposium 3.
REPORTING FROM CTAD
IDEAS study meets first aim of changing 3-month clinical management, health outcomes
BARCELONA – Amyloid PET brain imaging changed clinical management in 60% of patients with a diagnosis of mild cognitive impairment or dementia and confirmed a presumptive Alzheimer’s diagnosis in 95% of those with positive scans.
But the scans also benefited amyloid-negative patients, Gil Rabinovici, MD, said at the Clinical Trials on Alzheimer’s Disease conference. Before the test, 71% carried an Alzheimer’s disease (AD) diagnosis; after the test, just 10% did, opening the way for an accurate diagnosis and more effective treatment.
“These patients were saved from unnecessary treatment for Alzheimer’s,” said Dr. Rabinovici, the Edward Fein and Pearl Landrith Endowed Professor in Memory & Aging at the University of California, San Francisco. They received more suitable care plans because of the confirmation.
He presented final results of aim one of the IDEAS (Imaging Dementia–Evidence for Amyloid Scanning) study, which seeks to prove that amyloid imaging changes clinical management and improves health outcomes in Medicare beneficiaries who have been diagnosed with mild cognitive impairment (MCI) or dementia of uncertain cause. Its two aims are to show that amyloid PET imaging affects a patient’s care plan within 3 months of the scan and that this impacts major medical outcomes 12 months later. In diagnostically uncertain cases, investigators theorized, amyloid PET imaging would lead to significant changes in patient management, which would then translate into improved medical outcomes.
Ultimately, investigators hope the U.S.-wide, open-label study will prove the clinical value of amyloid PET scanning and convince the Centers for Medicare & Medicaid Services to make the test a fully covered service.
So far, IDEAS has accrued data on 11,409 patients and is quickly closing in on the 18,000-patient target. The patients reported on at CTAD were aged a mean of 75 years and were largely white; only 4% were black and 4% Hispanic. The mean Mini-Mental Scale Exam score was 26. AD was the leading suspect pathology in 73% of the 6,905 with MCI and in 83% of those with dementia of uncertain etiology. Overall, 44% were taking AD medications at baseline.
Scans were positive in 55% of those with MCI and in 70% of those with dementia. Overall, the scans changed clinical management in 61% (7,018), including 60% of those with MCI and 63% of those with dementia.
“We also asked physicians how much the scan results contributed to these changes, and 86.7% replied that they ‘contributed significantly,’ ” Dr. Rabinovici said.
Most changes involved adjustments to medication. AD drugs were started in 44% of MCI patients and in 45% of dementia patients, and non-AD drugs started in 22% and 25%, respectively. About a fifth of the patients received counseling in wake of the scan results.
Medication adjustments also varied by scan result. Among amyloid-positive MCI patients, AD drug use increased from 40% before imaging to 81% after; among amyloid-negative MCI patients, drug use decreased slightly from 27% to 24%. Among amyloid-positive dementia patients, AD drug use increased from 63% to 91%, and among amyloid-negative patients, it dropped from 50% to 44%. All these changes were statistically significant.
The primary diagnosis changed from AD to non-AD in 25%, and from non-AD to AD in 10%. Among amyloid-positive patients, the diagnosis prevalence jumped from 80.0% to 95.5%; among amyloid-negative patients, it dropped from 71% to just 10%.
“IDEAS now provides the strongest data we have supporting the beneficial impact of amyloid PET on patient management,” said Dr. Rabinovici. “Aim two, which is the 12-month health outcomes, we expect to be completed by the end of next year.”
The IDEAS team is also looking at a furthering the investigation with a study called, aptly, “NEW IDEAS.” That would reach out to recruit the minorities that were so underrepresented in the main study and include patients with early-onset MCI or dementia. Building up a library of DNA and blood plasma samples might also fit into the new project.
IDEAS is a funding collaboration of the CMS, the Alzheimer’s Association, Avid Radiopharmaceuticals/Eli Lilly, General Electric Healthcare, Piramal Imaging, and the American College of Radiology. Dr. Rabinovici had no financial disclosures.
BARCELONA – Amyloid PET brain imaging changed clinical management in 60% of patients with a diagnosis of mild cognitive impairment or dementia and confirmed a presumptive Alzheimer’s diagnosis in 95% of those with positive scans.
But the scans also benefited amyloid-negative patients, Gil Rabinovici, MD, said at the Clinical Trials on Alzheimer’s Disease conference. Before the test, 71% carried an Alzheimer’s disease (AD) diagnosis; after the test, just 10% did, opening the way for an accurate diagnosis and more effective treatment.
“These patients were saved from unnecessary treatment for Alzheimer’s,” said Dr. Rabinovici, the Edward Fein and Pearl Landrith Endowed Professor in Memory & Aging at the University of California, San Francisco. They received more suitable care plans because of the confirmation.
He presented final results of aim one of the IDEAS (Imaging Dementia–Evidence for Amyloid Scanning) study, which seeks to prove that amyloid imaging changes clinical management and improves health outcomes in Medicare beneficiaries who have been diagnosed with mild cognitive impairment (MCI) or dementia of uncertain cause. Its two aims are to show that amyloid PET imaging affects a patient’s care plan within 3 months of the scan and that this impacts major medical outcomes 12 months later. In diagnostically uncertain cases, investigators theorized, amyloid PET imaging would lead to significant changes in patient management, which would then translate into improved medical outcomes.
Ultimately, investigators hope the U.S.-wide, open-label study will prove the clinical value of amyloid PET scanning and convince the Centers for Medicare & Medicaid Services to make the test a fully covered service.
So far, IDEAS has accrued data on 11,409 patients and is quickly closing in on the 18,000-patient target. The patients reported on at CTAD were aged a mean of 75 years and were largely white; only 4% were black and 4% Hispanic. The mean Mini-Mental Scale Exam score was 26. AD was the leading suspect pathology in 73% of the 6,905 with MCI and in 83% of those with dementia of uncertain etiology. Overall, 44% were taking AD medications at baseline.
Scans were positive in 55% of those with MCI and in 70% of those with dementia. Overall, the scans changed clinical management in 61% (7,018), including 60% of those with MCI and 63% of those with dementia.
“We also asked physicians how much the scan results contributed to these changes, and 86.7% replied that they ‘contributed significantly,’ ” Dr. Rabinovici said.
Most changes involved adjustments to medication. AD drugs were started in 44% of MCI patients and in 45% of dementia patients, and non-AD drugs started in 22% and 25%, respectively. About a fifth of the patients received counseling in wake of the scan results.
Medication adjustments also varied by scan result. Among amyloid-positive MCI patients, AD drug use increased from 40% before imaging to 81% after; among amyloid-negative MCI patients, drug use decreased slightly from 27% to 24%. Among amyloid-positive dementia patients, AD drug use increased from 63% to 91%, and among amyloid-negative patients, it dropped from 50% to 44%. All these changes were statistically significant.
The primary diagnosis changed from AD to non-AD in 25%, and from non-AD to AD in 10%. Among amyloid-positive patients, the diagnosis prevalence jumped from 80.0% to 95.5%; among amyloid-negative patients, it dropped from 71% to just 10%.
“IDEAS now provides the strongest data we have supporting the beneficial impact of amyloid PET on patient management,” said Dr. Rabinovici. “Aim two, which is the 12-month health outcomes, we expect to be completed by the end of next year.”
The IDEAS team is also looking at a furthering the investigation with a study called, aptly, “NEW IDEAS.” That would reach out to recruit the minorities that were so underrepresented in the main study and include patients with early-onset MCI or dementia. Building up a library of DNA and blood plasma samples might also fit into the new project.
IDEAS is a funding collaboration of the CMS, the Alzheimer’s Association, Avid Radiopharmaceuticals/Eli Lilly, General Electric Healthcare, Piramal Imaging, and the American College of Radiology. Dr. Rabinovici had no financial disclosures.
BARCELONA – Amyloid PET brain imaging changed clinical management in 60% of patients with a diagnosis of mild cognitive impairment or dementia and confirmed a presumptive Alzheimer’s diagnosis in 95% of those with positive scans.
But the scans also benefited amyloid-negative patients, Gil Rabinovici, MD, said at the Clinical Trials on Alzheimer’s Disease conference. Before the test, 71% carried an Alzheimer’s disease (AD) diagnosis; after the test, just 10% did, opening the way for an accurate diagnosis and more effective treatment.
“These patients were saved from unnecessary treatment for Alzheimer’s,” said Dr. Rabinovici, the Edward Fein and Pearl Landrith Endowed Professor in Memory & Aging at the University of California, San Francisco. They received more suitable care plans because of the confirmation.
He presented final results of aim one of the IDEAS (Imaging Dementia–Evidence for Amyloid Scanning) study, which seeks to prove that amyloid imaging changes clinical management and improves health outcomes in Medicare beneficiaries who have been diagnosed with mild cognitive impairment (MCI) or dementia of uncertain cause. Its two aims are to show that amyloid PET imaging affects a patient’s care plan within 3 months of the scan and that this impacts major medical outcomes 12 months later. In diagnostically uncertain cases, investigators theorized, amyloid PET imaging would lead to significant changes in patient management, which would then translate into improved medical outcomes.
Ultimately, investigators hope the U.S.-wide, open-label study will prove the clinical value of amyloid PET scanning and convince the Centers for Medicare & Medicaid Services to make the test a fully covered service.
So far, IDEAS has accrued data on 11,409 patients and is quickly closing in on the 18,000-patient target. The patients reported on at CTAD were aged a mean of 75 years and were largely white; only 4% were black and 4% Hispanic. The mean Mini-Mental Scale Exam score was 26. AD was the leading suspect pathology in 73% of the 6,905 with MCI and in 83% of those with dementia of uncertain etiology. Overall, 44% were taking AD medications at baseline.
Scans were positive in 55% of those with MCI and in 70% of those with dementia. Overall, the scans changed clinical management in 61% (7,018), including 60% of those with MCI and 63% of those with dementia.
“We also asked physicians how much the scan results contributed to these changes, and 86.7% replied that they ‘contributed significantly,’ ” Dr. Rabinovici said.
Most changes involved adjustments to medication. AD drugs were started in 44% of MCI patients and in 45% of dementia patients, and non-AD drugs started in 22% and 25%, respectively. About a fifth of the patients received counseling in wake of the scan results.
Medication adjustments also varied by scan result. Among amyloid-positive MCI patients, AD drug use increased from 40% before imaging to 81% after; among amyloid-negative MCI patients, drug use decreased slightly from 27% to 24%. Among amyloid-positive dementia patients, AD drug use increased from 63% to 91%, and among amyloid-negative patients, it dropped from 50% to 44%. All these changes were statistically significant.
The primary diagnosis changed from AD to non-AD in 25%, and from non-AD to AD in 10%. Among amyloid-positive patients, the diagnosis prevalence jumped from 80.0% to 95.5%; among amyloid-negative patients, it dropped from 71% to just 10%.
“IDEAS now provides the strongest data we have supporting the beneficial impact of amyloid PET on patient management,” said Dr. Rabinovici. “Aim two, which is the 12-month health outcomes, we expect to be completed by the end of next year.”
The IDEAS team is also looking at a furthering the investigation with a study called, aptly, “NEW IDEAS.” That would reach out to recruit the minorities that were so underrepresented in the main study and include patients with early-onset MCI or dementia. Building up a library of DNA and blood plasma samples might also fit into the new project.
IDEAS is a funding collaboration of the CMS, the Alzheimer’s Association, Avid Radiopharmaceuticals/Eli Lilly, General Electric Healthcare, Piramal Imaging, and the American College of Radiology. Dr. Rabinovici had no financial disclosures.
REPORTING FROM CTAD
Key clinical point: Amyloid PET imaging can refine equivocal dementia diagnoses.
Major finding:
Study details: The IDEAS study has thus far accrued data on 11,409 subjects.
Disclosures: IDEAS is a funding collaboration of the Centers for Medicare & Medicaid Services, the Alzheimer’s Association, Avid Radiopharmaceuticals/Eli Lilly, General Electric Healthcare, Piramal Imaging, and the American College of Radiology. Dr. Rabinovici had no financial disclosures.
Retinal thinning in aquaporin-4-positive NMOSD may occur without optic neuritis
BERLIN – Retinal thinning related to ganglion loss may be independent of optic neuritis attacks in patients with neuromyelitis optica spectrum disorders who have anti–aquaporin-4 antibodies.
These eyes exhibited an annual retinal volume loss of about 0.6 micrometers – 80 times higher than that of normal controls – even though they did not have a history of optic neuritis (ON), Frederike C. Oertel said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
“The most likely explanation for this seems to be a disease-related primary retinopathy due to the high density of astrocytic cells in the retina and the afferent visual system,” said Ms. Oertel, a doctoral student at NeuroCure Clinical Research Center, Berlin.
The study appeared in the Journal of Neurology, Neurosurgery & Psychiatry (J Neurol Neurosurg Psychiatry. 2018 Jun 19. doi: 10.1136/jnnp-2018-318382).
A previous cross-sectional study by her group found retinal thinning and an alteration of foveal shape in anti–aquaporin-4 (anti-AQP4) positive patients with neuromyelitis optica spectrum disorders (NMOSD) independent of whether they had experienced a clinical attack of optic neuritis (Neurol Neuroimmunol Neuroinflamm. 2017 May;4[3]:e334). In these patients, the fovea changed shape from a characteristic steeply angled “V” to a broader, flatter “U” shape, she said.
In that 2017 paper, Ms. Oertel and her colleagues theorized that the relationship between the water-channel regulator AQP4 and astrocytes could be the root cause of these microstructural alterations.
“The parafoveal area is characterized by a high density of retinal astrocytic Müller cells, which express AQP4 and may thus serve as retinal targets in NMOSD,” they wrote. “Müller cells regulate the retinal water balance and have a relevant role in neurotransmitter and photopigment recycling, as well as in energy and lipid metabolism. Müller cell dysfunction or degeneration could thus lead to impaired retinal function including changes in water homeostasis. Of interest, both the initial cohort and the confirmatory cohort showed a mild increase of peripapillary retinal nerve fiber layer thickness, which could indicate tissue swelling. These findings are supported by animal studies showing retraction of astrocytic end feet in some and astrocyte death in other cases, suggesting a primary astrocytoma in NMOSD also outside acute lesions.”
The study Ms. Oertel presented at ECTRIMS looked at full retinal thickness using the same imaging tool, optical coherence tomography (OCT). The longitudinal cohort comprised 94 eyes in 51 anti–AQP4-IgG seropositive patients who had NMOSD; 60 of these eyes had experienced an optic neuritis attack and 34 had not. Most of the patients were female; the mean age was 47 years. They were compared against 28 age- and sex-matched healthy controls.
OCT measured combined ganglion cell and inner plexiform layer (GCIP), the peripapillary retinal nerve fiber layer (pRNFL), fovea thickness (FT), inner nuclear layer (INL), and total macular volume (TMV).
At baseline, ON eyes already displayed reduced GCIP, FT, and TMV, compared with healthy controls – but so had eyes that had not had ON. Over the follow-up period, eyes without ON continued to show thinning, even in the absence of a clinical attack. Although visual acuity didn’t change over time, the retinas continued to thin, losing an average of 0.6 micrometers each year, a rate 80 times greater than that seen in the control group.
“We saw this significant loss of the ganglion cell layer volume independent of ON, suggesting that retinal neurodegeneration is not dependent on ON in these patients,” Ms. Oertel said.
The results fit well into the group’s prior theory of astrocytic involvement. However, she added, “We still have to think about an alternative theory of drug-induced neuroaxonal damage and retrograde neuroaxonal degeneration.”
The project was supported with grants from the German Ministry for Education and Research. Ms. Oertel had no financial disclosures relevant to the work, but many coauthors reported financial relationships with industry.
BERLIN – Retinal thinning related to ganglion loss may be independent of optic neuritis attacks in patients with neuromyelitis optica spectrum disorders who have anti–aquaporin-4 antibodies.
These eyes exhibited an annual retinal volume loss of about 0.6 micrometers – 80 times higher than that of normal controls – even though they did not have a history of optic neuritis (ON), Frederike C. Oertel said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
“The most likely explanation for this seems to be a disease-related primary retinopathy due to the high density of astrocytic cells in the retina and the afferent visual system,” said Ms. Oertel, a doctoral student at NeuroCure Clinical Research Center, Berlin.
The study appeared in the Journal of Neurology, Neurosurgery & Psychiatry (J Neurol Neurosurg Psychiatry. 2018 Jun 19. doi: 10.1136/jnnp-2018-318382).
A previous cross-sectional study by her group found retinal thinning and an alteration of foveal shape in anti–aquaporin-4 (anti-AQP4) positive patients with neuromyelitis optica spectrum disorders (NMOSD) independent of whether they had experienced a clinical attack of optic neuritis (Neurol Neuroimmunol Neuroinflamm. 2017 May;4[3]:e334). In these patients, the fovea changed shape from a characteristic steeply angled “V” to a broader, flatter “U” shape, she said.
In that 2017 paper, Ms. Oertel and her colleagues theorized that the relationship between the water-channel regulator AQP4 and astrocytes could be the root cause of these microstructural alterations.
“The parafoveal area is characterized by a high density of retinal astrocytic Müller cells, which express AQP4 and may thus serve as retinal targets in NMOSD,” they wrote. “Müller cells regulate the retinal water balance and have a relevant role in neurotransmitter and photopigment recycling, as well as in energy and lipid metabolism. Müller cell dysfunction or degeneration could thus lead to impaired retinal function including changes in water homeostasis. Of interest, both the initial cohort and the confirmatory cohort showed a mild increase of peripapillary retinal nerve fiber layer thickness, which could indicate tissue swelling. These findings are supported by animal studies showing retraction of astrocytic end feet in some and astrocyte death in other cases, suggesting a primary astrocytoma in NMOSD also outside acute lesions.”
The study Ms. Oertel presented at ECTRIMS looked at full retinal thickness using the same imaging tool, optical coherence tomography (OCT). The longitudinal cohort comprised 94 eyes in 51 anti–AQP4-IgG seropositive patients who had NMOSD; 60 of these eyes had experienced an optic neuritis attack and 34 had not. Most of the patients were female; the mean age was 47 years. They were compared against 28 age- and sex-matched healthy controls.
OCT measured combined ganglion cell and inner plexiform layer (GCIP), the peripapillary retinal nerve fiber layer (pRNFL), fovea thickness (FT), inner nuclear layer (INL), and total macular volume (TMV).
At baseline, ON eyes already displayed reduced GCIP, FT, and TMV, compared with healthy controls – but so had eyes that had not had ON. Over the follow-up period, eyes without ON continued to show thinning, even in the absence of a clinical attack. Although visual acuity didn’t change over time, the retinas continued to thin, losing an average of 0.6 micrometers each year, a rate 80 times greater than that seen in the control group.
“We saw this significant loss of the ganglion cell layer volume independent of ON, suggesting that retinal neurodegeneration is not dependent on ON in these patients,” Ms. Oertel said.
The results fit well into the group’s prior theory of astrocytic involvement. However, she added, “We still have to think about an alternative theory of drug-induced neuroaxonal damage and retrograde neuroaxonal degeneration.”
The project was supported with grants from the German Ministry for Education and Research. Ms. Oertel had no financial disclosures relevant to the work, but many coauthors reported financial relationships with industry.
BERLIN – Retinal thinning related to ganglion loss may be independent of optic neuritis attacks in patients with neuromyelitis optica spectrum disorders who have anti–aquaporin-4 antibodies.
These eyes exhibited an annual retinal volume loss of about 0.6 micrometers – 80 times higher than that of normal controls – even though they did not have a history of optic neuritis (ON), Frederike C. Oertel said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
“The most likely explanation for this seems to be a disease-related primary retinopathy due to the high density of astrocytic cells in the retina and the afferent visual system,” said Ms. Oertel, a doctoral student at NeuroCure Clinical Research Center, Berlin.
The study appeared in the Journal of Neurology, Neurosurgery & Psychiatry (J Neurol Neurosurg Psychiatry. 2018 Jun 19. doi: 10.1136/jnnp-2018-318382).
A previous cross-sectional study by her group found retinal thinning and an alteration of foveal shape in anti–aquaporin-4 (anti-AQP4) positive patients with neuromyelitis optica spectrum disorders (NMOSD) independent of whether they had experienced a clinical attack of optic neuritis (Neurol Neuroimmunol Neuroinflamm. 2017 May;4[3]:e334). In these patients, the fovea changed shape from a characteristic steeply angled “V” to a broader, flatter “U” shape, she said.
In that 2017 paper, Ms. Oertel and her colleagues theorized that the relationship between the water-channel regulator AQP4 and astrocytes could be the root cause of these microstructural alterations.
“The parafoveal area is characterized by a high density of retinal astrocytic Müller cells, which express AQP4 and may thus serve as retinal targets in NMOSD,” they wrote. “Müller cells regulate the retinal water balance and have a relevant role in neurotransmitter and photopigment recycling, as well as in energy and lipid metabolism. Müller cell dysfunction or degeneration could thus lead to impaired retinal function including changes in water homeostasis. Of interest, both the initial cohort and the confirmatory cohort showed a mild increase of peripapillary retinal nerve fiber layer thickness, which could indicate tissue swelling. These findings are supported by animal studies showing retraction of astrocytic end feet in some and astrocyte death in other cases, suggesting a primary astrocytoma in NMOSD also outside acute lesions.”
The study Ms. Oertel presented at ECTRIMS looked at full retinal thickness using the same imaging tool, optical coherence tomography (OCT). The longitudinal cohort comprised 94 eyes in 51 anti–AQP4-IgG seropositive patients who had NMOSD; 60 of these eyes had experienced an optic neuritis attack and 34 had not. Most of the patients were female; the mean age was 47 years. They were compared against 28 age- and sex-matched healthy controls.
OCT measured combined ganglion cell and inner plexiform layer (GCIP), the peripapillary retinal nerve fiber layer (pRNFL), fovea thickness (FT), inner nuclear layer (INL), and total macular volume (TMV).
At baseline, ON eyes already displayed reduced GCIP, FT, and TMV, compared with healthy controls – but so had eyes that had not had ON. Over the follow-up period, eyes without ON continued to show thinning, even in the absence of a clinical attack. Although visual acuity didn’t change over time, the retinas continued to thin, losing an average of 0.6 micrometers each year, a rate 80 times greater than that seen in the control group.
“We saw this significant loss of the ganglion cell layer volume independent of ON, suggesting that retinal neurodegeneration is not dependent on ON in these patients,” Ms. Oertel said.
The results fit well into the group’s prior theory of astrocytic involvement. However, she added, “We still have to think about an alternative theory of drug-induced neuroaxonal damage and retrograde neuroaxonal degeneration.”
The project was supported with grants from the German Ministry for Education and Research. Ms. Oertel had no financial disclosures relevant to the work, but many coauthors reported financial relationships with industry.
REPORTING FROM ECTRIMS 2018
Key clinical point:
Major finding: Over 2.5 years retinas thinned an average of 0.6 micrometers annually.
Study details: The longitudinal study comprised 94 eyes.
Disclosures: The project was supported with grants from the German Ministry for Education and Research. Dr. Oertel had no conflicts of interest, but many coauthors reported financial relationships with industry.
Source: Oertel FC et al. ECTRIMS 2018, Abstract 212.
Investigational BTK inhibitor for relapsing MS advances on positive phase 2 data
BERLIN – Evobrutinib, an investigational inhibitor of Bruton’s tyrosine kinase (BTK), significantly reduced the number of new T1 gadolinium-enhancing lesions at 24 weeks compared with placebo in patients with relapsing multiples sclerosis (MS).
However, the molecule was also associated with grade 3 and 4 elevations in alanine aminotransferase – a troubling finding, Xavier Montalban, MD, said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
“Fortunately, all patients were asymptomatic, and the elevations were completely reversible. The results of this trial do support further development of this molecule,” said Dr. Montalban, director of the Multiple Sclerosis Centre of Catalonia at the Vall d’Hebron University Hospital in Barcelona.
Evobrutinib exerts a dual action in MS, Dr. Montalban said. By inhibiting BTK, the drug blocks B-cell activation and interaction between B and T cells. It also inhibits macrophage survival and dampens cytokine release, he said.
The study randomized 213 patients with relapsing MS to placebo or to evobrutinib in three daily doses: 25 mg, 75 mg, or 150 mg. A control arm of 54 additional patients received treatment with dimethyl fumarate. After 24 weeks of randomized treatment, patients who got placebo switched to 25 mg per day; everyone else continued in their assigned groups for another 24 weeks. The study concluded with an open-label extension phase during which everyone took 75 mg daily.
Dr. Montalban reported the primary 24-week analysis. The remainder of the data has not been analyzed yet, he said. The primary endpoint was the total number of T1 gadolinium-enhancing lesions at weeks 12, 16, 20, and 24. Secondary endpoints included the 24-week annualized relapse rate and safety signals. Patients were a mean of 41 years old, with a mean disease duration of 10 years. They had experienced a mean of two relapses in the prior 2 years. About 20% had gadolinium-enhancing lesions at baseline.
Compared with placebo and with the 25-mg dose, evobrutinib 75 mg and 150 mg significantly reduced the number of new enhancing lesions at 24 weeks. There was evidence of a dose-response effect, Dr. Montalban said. Patients taking placebo developed a mean of 3.8 new lesions, while those on 75 mg developed a mean of 1.69 and those taking 150 mg, a mean of 1.15. Patients in the 25-mg group developed a mean of four new lesions – not significantly different than placebo.
Both the 75-mg and 150-mg doses decreased the annualized relapse rate, compared with placebo but missed statistical significance, with P values of 0.90 and 0.63, respectively.
These two doses also conferred significant benefit on two other secondary endpoints, significantly reducing the number of new or enlarging T2 lesions and reducing the total T2 lesion volume, compared with placebo.
The safety profile was relatively benign, with no infections, including no opportunistic infections, and no neoplasms. About 7% of the highest-dose group experienced nausea, and the same number, arthralgia. Seven patients taking evobrutinib experienced grade 1 lymphopenia, compared with three patients taking placebo; grade 2 lymphopenia developed in one patient in the highest-dose group.
ALT elevation was the most concerning adverse event, Dr. Montalban said. Grade 1 elevations developed in 17% of the low-dose group and about 22% of the other two active groups (11 patients each), compared with 7% of the placebo group. Grade 2 elevations developed in three placebo patients and in two taking the highest dose of evobrutinib. There was one grade 3 elevation, which occurred in a patient in the highest-dose group. These were asymptomatic and resolved after discontinuing the medication. Lipase and aspartate transaminase elevations were also associated with evobrutinib, but Dr. Montalban did not provide these details.
He has been a paid consultant for Merck Serono, which is developing evobrutinib.
SOURCE: Montalban X et al. ECTRIMS 2018. Abstract 322.
BERLIN – Evobrutinib, an investigational inhibitor of Bruton’s tyrosine kinase (BTK), significantly reduced the number of new T1 gadolinium-enhancing lesions at 24 weeks compared with placebo in patients with relapsing multiples sclerosis (MS).
However, the molecule was also associated with grade 3 and 4 elevations in alanine aminotransferase – a troubling finding, Xavier Montalban, MD, said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
“Fortunately, all patients were asymptomatic, and the elevations were completely reversible. The results of this trial do support further development of this molecule,” said Dr. Montalban, director of the Multiple Sclerosis Centre of Catalonia at the Vall d’Hebron University Hospital in Barcelona.
Evobrutinib exerts a dual action in MS, Dr. Montalban said. By inhibiting BTK, the drug blocks B-cell activation and interaction between B and T cells. It also inhibits macrophage survival and dampens cytokine release, he said.
The study randomized 213 patients with relapsing MS to placebo or to evobrutinib in three daily doses: 25 mg, 75 mg, or 150 mg. A control arm of 54 additional patients received treatment with dimethyl fumarate. After 24 weeks of randomized treatment, patients who got placebo switched to 25 mg per day; everyone else continued in their assigned groups for another 24 weeks. The study concluded with an open-label extension phase during which everyone took 75 mg daily.
Dr. Montalban reported the primary 24-week analysis. The remainder of the data has not been analyzed yet, he said. The primary endpoint was the total number of T1 gadolinium-enhancing lesions at weeks 12, 16, 20, and 24. Secondary endpoints included the 24-week annualized relapse rate and safety signals. Patients were a mean of 41 years old, with a mean disease duration of 10 years. They had experienced a mean of two relapses in the prior 2 years. About 20% had gadolinium-enhancing lesions at baseline.
Compared with placebo and with the 25-mg dose, evobrutinib 75 mg and 150 mg significantly reduced the number of new enhancing lesions at 24 weeks. There was evidence of a dose-response effect, Dr. Montalban said. Patients taking placebo developed a mean of 3.8 new lesions, while those on 75 mg developed a mean of 1.69 and those taking 150 mg, a mean of 1.15. Patients in the 25-mg group developed a mean of four new lesions – not significantly different than placebo.
Both the 75-mg and 150-mg doses decreased the annualized relapse rate, compared with placebo but missed statistical significance, with P values of 0.90 and 0.63, respectively.
These two doses also conferred significant benefit on two other secondary endpoints, significantly reducing the number of new or enlarging T2 lesions and reducing the total T2 lesion volume, compared with placebo.
The safety profile was relatively benign, with no infections, including no opportunistic infections, and no neoplasms. About 7% of the highest-dose group experienced nausea, and the same number, arthralgia. Seven patients taking evobrutinib experienced grade 1 lymphopenia, compared with three patients taking placebo; grade 2 lymphopenia developed in one patient in the highest-dose group.
ALT elevation was the most concerning adverse event, Dr. Montalban said. Grade 1 elevations developed in 17% of the low-dose group and about 22% of the other two active groups (11 patients each), compared with 7% of the placebo group. Grade 2 elevations developed in three placebo patients and in two taking the highest dose of evobrutinib. There was one grade 3 elevation, which occurred in a patient in the highest-dose group. These were asymptomatic and resolved after discontinuing the medication. Lipase and aspartate transaminase elevations were also associated with evobrutinib, but Dr. Montalban did not provide these details.
He has been a paid consultant for Merck Serono, which is developing evobrutinib.
SOURCE: Montalban X et al. ECTRIMS 2018. Abstract 322.
BERLIN – Evobrutinib, an investigational inhibitor of Bruton’s tyrosine kinase (BTK), significantly reduced the number of new T1 gadolinium-enhancing lesions at 24 weeks compared with placebo in patients with relapsing multiples sclerosis (MS).
However, the molecule was also associated with grade 3 and 4 elevations in alanine aminotransferase – a troubling finding, Xavier Montalban, MD, said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
“Fortunately, all patients were asymptomatic, and the elevations were completely reversible. The results of this trial do support further development of this molecule,” said Dr. Montalban, director of the Multiple Sclerosis Centre of Catalonia at the Vall d’Hebron University Hospital in Barcelona.
Evobrutinib exerts a dual action in MS, Dr. Montalban said. By inhibiting BTK, the drug blocks B-cell activation and interaction between B and T cells. It also inhibits macrophage survival and dampens cytokine release, he said.
The study randomized 213 patients with relapsing MS to placebo or to evobrutinib in three daily doses: 25 mg, 75 mg, or 150 mg. A control arm of 54 additional patients received treatment with dimethyl fumarate. After 24 weeks of randomized treatment, patients who got placebo switched to 25 mg per day; everyone else continued in their assigned groups for another 24 weeks. The study concluded with an open-label extension phase during which everyone took 75 mg daily.
Dr. Montalban reported the primary 24-week analysis. The remainder of the data has not been analyzed yet, he said. The primary endpoint was the total number of T1 gadolinium-enhancing lesions at weeks 12, 16, 20, and 24. Secondary endpoints included the 24-week annualized relapse rate and safety signals. Patients were a mean of 41 years old, with a mean disease duration of 10 years. They had experienced a mean of two relapses in the prior 2 years. About 20% had gadolinium-enhancing lesions at baseline.
Compared with placebo and with the 25-mg dose, evobrutinib 75 mg and 150 mg significantly reduced the number of new enhancing lesions at 24 weeks. There was evidence of a dose-response effect, Dr. Montalban said. Patients taking placebo developed a mean of 3.8 new lesions, while those on 75 mg developed a mean of 1.69 and those taking 150 mg, a mean of 1.15. Patients in the 25-mg group developed a mean of four new lesions – not significantly different than placebo.
Both the 75-mg and 150-mg doses decreased the annualized relapse rate, compared with placebo but missed statistical significance, with P values of 0.90 and 0.63, respectively.
These two doses also conferred significant benefit on two other secondary endpoints, significantly reducing the number of new or enlarging T2 lesions and reducing the total T2 lesion volume, compared with placebo.
The safety profile was relatively benign, with no infections, including no opportunistic infections, and no neoplasms. About 7% of the highest-dose group experienced nausea, and the same number, arthralgia. Seven patients taking evobrutinib experienced grade 1 lymphopenia, compared with three patients taking placebo; grade 2 lymphopenia developed in one patient in the highest-dose group.
ALT elevation was the most concerning adverse event, Dr. Montalban said. Grade 1 elevations developed in 17% of the low-dose group and about 22% of the other two active groups (11 patients each), compared with 7% of the placebo group. Grade 2 elevations developed in three placebo patients and in two taking the highest dose of evobrutinib. There was one grade 3 elevation, which occurred in a patient in the highest-dose group. These were asymptomatic and resolved after discontinuing the medication. Lipase and aspartate transaminase elevations were also associated with evobrutinib, but Dr. Montalban did not provide these details.
He has been a paid consultant for Merck Serono, which is developing evobrutinib.
SOURCE: Montalban X et al. ECTRIMS 2018. Abstract 322.
REPORTING FROM ECTRIMS 2018
Key clinical point: Evobrutinib reduced the number of new T1 gadolinium-enhancing lesions.
Major finding: At 24 weeks, the 150-mg group had a mean of 1.15 new lesions vs. 3.8 in the placebo group.
Study details: The phase 2 study randomized 213 patients.
Disclosures: Dr. Montalban has been a paid consultant for Merck Serono, which is developing the molecule.
Source: Montalban X et al. ECTRIMS 2018.Abstract 322.
Novel IL-6 antibody slashes relapse rates in neuromyelitis optica
BERLIN – The monoclonal antibody satralizumab reduced by 62% relapses of neuromyelitis optica spectrum disorder (NMOSD) over 24 weeks, as compared with placebo.
Chugai Pharmaceuticals of Tokyo and Roche are codeveloping the molecule. Called a “recycling” antibody, it has been designed to have extended circulation in plasma, Dr. Yamamura said.
The SAkuraSky study randomized 83 patients to placebo or to subcutaneous satralizumab 120 mg at baseline and weeks 2 and 4, and then once a month for 20 months.
Patients in the study had either aquaporin-4–positive NMOSD or neuromyelitis optica with or without aquaporin-4 antibodies. They also had to have experienced at least two relapses in the past 2 years, at least one of which occurred in the last year. The primary endpoint was time to first relapse during the randomized phase.
Patients were a mean of about 42 years old. A total of 64% were diagnosed with neuromyelitis optica and the remainder with NMOSD, with a mean disease duration of about 5 years. Aquaporin-4 antibodies were present in 67%. The baseline annualized relapse rate was 1.4. Baseline medications included azathioprine, mycophenolate, and oral corticosteroids. Patients stayed on these throughout the study.
Relapse curves separated significantly by 36 weeks, with 89% of treated patients being relapse-free vs. 66% of placebo patients. At 96 weeks, the curves still favored satralizumab, with 77.6% vs. 58.7% without relapse. The trajectories held steady until the end of follow-up at 216 weeks (relapse-free rates 60% vs. 30%; HR 0.38). The difference amounted to a risk reduction of 62%.
The antibody was even more effective for aquaporin-4–positive patients. By 48 weeks, the relapse-free rates were 91.5% vs. 60%. By week 96, 91.5% of treated patients were still without relapse compared to 53.3% of placebo patients. By week 216, those numbers were about 70% vs. 20%, for a 79% risk reduction. Treatment was still significantly better than placebo for aquaporin negative patients, but the benefit was less dramatic (67% vs. 56%; RR 34%).
The rate of serious infections was similar between placebo and satralizumab (62% vs. 68%) with no serious opportunistic infections in either group. Injection site reactions were more common among patients taking satralizumab (12% vs. 5%). Neoplasms occurred in 7% of each group.
Development of the molecule will continue, Dr. Yamamura said.
Chugai Pharmaceuticals sponsored the study. Dr. Yamamura has served as a consultant for the company and reported financial ties with numerous other drug manufacturers.
SOURCE: Yamamura T et al. ECTRIMS 2018, Oral abstract 323
BERLIN – The monoclonal antibody satralizumab reduced by 62% relapses of neuromyelitis optica spectrum disorder (NMOSD) over 24 weeks, as compared with placebo.
Chugai Pharmaceuticals of Tokyo and Roche are codeveloping the molecule. Called a “recycling” antibody, it has been designed to have extended circulation in plasma, Dr. Yamamura said.
The SAkuraSky study randomized 83 patients to placebo or to subcutaneous satralizumab 120 mg at baseline and weeks 2 and 4, and then once a month for 20 months.
Patients in the study had either aquaporin-4–positive NMOSD or neuromyelitis optica with or without aquaporin-4 antibodies. They also had to have experienced at least two relapses in the past 2 years, at least one of which occurred in the last year. The primary endpoint was time to first relapse during the randomized phase.
Patients were a mean of about 42 years old. A total of 64% were diagnosed with neuromyelitis optica and the remainder with NMOSD, with a mean disease duration of about 5 years. Aquaporin-4 antibodies were present in 67%. The baseline annualized relapse rate was 1.4. Baseline medications included azathioprine, mycophenolate, and oral corticosteroids. Patients stayed on these throughout the study.
Relapse curves separated significantly by 36 weeks, with 89% of treated patients being relapse-free vs. 66% of placebo patients. At 96 weeks, the curves still favored satralizumab, with 77.6% vs. 58.7% without relapse. The trajectories held steady until the end of follow-up at 216 weeks (relapse-free rates 60% vs. 30%; HR 0.38). The difference amounted to a risk reduction of 62%.
The antibody was even more effective for aquaporin-4–positive patients. By 48 weeks, the relapse-free rates were 91.5% vs. 60%. By week 96, 91.5% of treated patients were still without relapse compared to 53.3% of placebo patients. By week 216, those numbers were about 70% vs. 20%, for a 79% risk reduction. Treatment was still significantly better than placebo for aquaporin negative patients, but the benefit was less dramatic (67% vs. 56%; RR 34%).
The rate of serious infections was similar between placebo and satralizumab (62% vs. 68%) with no serious opportunistic infections in either group. Injection site reactions were more common among patients taking satralizumab (12% vs. 5%). Neoplasms occurred in 7% of each group.
Development of the molecule will continue, Dr. Yamamura said.
Chugai Pharmaceuticals sponsored the study. Dr. Yamamura has served as a consultant for the company and reported financial ties with numerous other drug manufacturers.
SOURCE: Yamamura T et al. ECTRIMS 2018, Oral abstract 323
BERLIN – The monoclonal antibody satralizumab reduced by 62% relapses of neuromyelitis optica spectrum disorder (NMOSD) over 24 weeks, as compared with placebo.
Chugai Pharmaceuticals of Tokyo and Roche are codeveloping the molecule. Called a “recycling” antibody, it has been designed to have extended circulation in plasma, Dr. Yamamura said.
The SAkuraSky study randomized 83 patients to placebo or to subcutaneous satralizumab 120 mg at baseline and weeks 2 and 4, and then once a month for 20 months.
Patients in the study had either aquaporin-4–positive NMOSD or neuromyelitis optica with or without aquaporin-4 antibodies. They also had to have experienced at least two relapses in the past 2 years, at least one of which occurred in the last year. The primary endpoint was time to first relapse during the randomized phase.
Patients were a mean of about 42 years old. A total of 64% were diagnosed with neuromyelitis optica and the remainder with NMOSD, with a mean disease duration of about 5 years. Aquaporin-4 antibodies were present in 67%. The baseline annualized relapse rate was 1.4. Baseline medications included azathioprine, mycophenolate, and oral corticosteroids. Patients stayed on these throughout the study.
Relapse curves separated significantly by 36 weeks, with 89% of treated patients being relapse-free vs. 66% of placebo patients. At 96 weeks, the curves still favored satralizumab, with 77.6% vs. 58.7% without relapse. The trajectories held steady until the end of follow-up at 216 weeks (relapse-free rates 60% vs. 30%; HR 0.38). The difference amounted to a risk reduction of 62%.
The antibody was even more effective for aquaporin-4–positive patients. By 48 weeks, the relapse-free rates were 91.5% vs. 60%. By week 96, 91.5% of treated patients were still without relapse compared to 53.3% of placebo patients. By week 216, those numbers were about 70% vs. 20%, for a 79% risk reduction. Treatment was still significantly better than placebo for aquaporin negative patients, but the benefit was less dramatic (67% vs. 56%; RR 34%).
The rate of serious infections was similar between placebo and satralizumab (62% vs. 68%) with no serious opportunistic infections in either group. Injection site reactions were more common among patients taking satralizumab (12% vs. 5%). Neoplasms occurred in 7% of each group.
Development of the molecule will continue, Dr. Yamamura said.
Chugai Pharmaceuticals sponsored the study. Dr. Yamamura has served as a consultant for the company and reported financial ties with numerous other drug manufacturers.
SOURCE: Yamamura T et al. ECTRIMS 2018, Oral abstract 323
REPORTING FROM ECTRIMS 2018
Key clinical point: Satralizumab decreased relapse in all patients, but was more effective in those positive for aquaporin-4 antibodies.
Major finding: Compared with placebo, the antibody decreased relapse by 62% overall, and by 79% in aquaporin-4–positive patients.
Study details: A randomized, placebo-controlled study of 83 patients.
Disclosures: Chugai Pharmaceuticals sponsored the study. Dr. Yamamura has served as a consultant for the company and reported financial ties with numerous other drug manufacturers.
Source: Yamamura T et al. ECTRIMS 2018, Oral abstract 323.